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REVIEW ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 2  |  Page : 193-197

Thrombocytosis in gynecological cancers


Department of Radiation Oncology, VMMC and Safdarjung Hospital, New Delhi, India

Date of Web Publication23-Jun-2017

Correspondence Address:
Deepti Sharma
VMMC and Safdarjung Hospital, Room No 264, Second Floor, New OPD Block, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.189234

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 > Abstract 

Thrombocytosis has been suggested to be a poor prognostic indicator in malignancies. Studies have shown that thrombocytosis is associated with a poor prognosis in various gynecological malignancies such as carcinoma ovary, cervical cancer, and endometrial cancer. The aim of this study is to analyze the impact of thrombocytosis on the prognosis of gynecological cancer. All the relevant data were retrieved by PubMed, MEDLINE, and Web of Science, and then studies were chosen in this analysis of association between thrombocytosis and gynecological malignancy. Thrombocytosis is common in advanced disease in patients with ovarian cancer, endometrial cancer, and cervical cancer. Therefore, it may be a marker of tumor burden or biologically more aggressive disease. Thrombocytosis is bad prognostic factor and associated with poorer outcomes.

Keywords: Gynecological malignancy, platelets, poor prognosis, thrombocytosis


How to cite this article:
Sharma D, Singh G. Thrombocytosis in gynecological cancers. J Can Res Ther 2017;13:193-7

How to cite this URL:
Sharma D, Singh G. Thrombocytosis in gynecological cancers. J Can Res Ther [serial online] 2017 [cited 2019 Nov 13];13:193-7. Available from: http://www.cancerjournal.net/text.asp?2017/13/2/193/189234


 > Introduction Top


The association of thrombocytosis with malignancies has been known for more than 100 years.[1] Thrombocytosis was reported in patients with lung [2] colon [2] renal cell carcinomas,[3] cervical cancer,[4],[5] ovarian cancer,[6] and vulvar cancers.[7] We conducted MEDLINE and PubMed search of literature on the prognostic impact of thrombocytosis in gynecological cancer. References of all publication were also searched. The aim of this study is to analyze the impact of thrombocytosis on the prognosis of gynecological cancer.


 > Etiopathology of Thrombocytosis Top


Thrombocytosis is defined as an elevated platelet counts above 4.5 × 109/L. Platelets are small, irregularly shaped anuclear cell fragments which are derived from fragmentation of precursor megakaryocytes.[8] Their production is regulated by thrombopoietin (TPO), a hormone usually produced by the liver and kidneys.[9] Old platelets are destroyed by phagocytosis in the spleen and by Kupffer cells in the liver.


 > Interaction of Tumor Cells and Platelets Top


Platelets participate in tumor progression by contributing to the metastatic cascade, protecting tumor cells from immune surveillance, regulating tumor cell invasion, and angiogenesis.[10],[11] Thrombin is being generated either by direct contact with platelets or indirectly by stimulating tissue factor-mediated activation of the coagulation system.[12] The ovarian cancer-induced platelet activation is mediated by adenosine 59-diphosphate released from tumor cells and can be blocked by adenosine 59-diphosphate receptor (P2Y12 and P2Y1) antagonists.[13] Certain studies have also shown that tumor cells could lead to secretion of dense granules containing adenine nucleotides via the platelet Fcg receptor IIa.[14] Platelet activation by tumors throughout all phases of the metastatic cascade leads to the release of platelet-derived factors stored in their granules leading to inflammatory, proliferative, and proangiogenic activities of platelets to promote tumor growth, tissue invasion, and metastasis.[15] The platelets secrete thrombospondin-1 which facilitates the adhesion of tumor cells to the endothelium and promotes extravasations in the metastatic cascade.[16] The thrombospondin levels have found to be elevated in women with gynecologic malignancies. Once the tumor cells have exited circulation, factors derived from activated platelets are able to induce neoangiogenesis, thereby enabling growth at the metastatic site.[17]

Reactive or secondary thrombocytosis associated with malignancies has been established since the early 1870s, with an incidence of 10–57%.[16] Possible mechanisms include an overproduction of cytokines/growth factors stimulating megakaryocytes and their precursors. Serum interleukin (IL-6) is increased in most patients with reactive thrombocytosis, and elevation of this cytokine has been detected in a significant number of patients with cancer. Bone marrow endothelial cells, kidney, and spleen are capable of TPO production. TPO is produced and released into the circulation at a constant rate by the liver.[18] Normal physiology of platelet production involves the clearance of TPO by high-affinity TPO receptors on platelets and formation of a steady TPO concentration, thereby providing a basal stimulation of bone marrow megakaryocytes and normal rate of platelet production. However, in secondary thrombocytosis that can occur with malignancies, there can be upregulation of TPO production by the liver causing enhanced thrombopoiesis. Plasma TPO levels have also been shown to correlate with IL-6.[19] Platelets have capabilities to enhance sequestration, adherence, and penetration of malignant cells through the endothelial wall.[16] They may also prevent the immune system from clearing tumor cells from the circulatory system. Tumor growth depends on the formation of new blood vessels from preexisting capillaries (i.e., angiogenesis).[20] Tumor angiogenesis depends not only on endothelial cells and cancer cells but also on platelet-endothelium interactions. Platelets adhere to the tumor-related endothelium and release high concentrations of vascular endothelial growth factor (VEGF), which is a potent stimulator of angiogenesis.

Platelet granules contain a variety of factors such as VEGF, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor beta (TGF-β), IL-6, thrombin, and fibrinogen.[21] These modulators are secreted immediately after platelet activation, and many have been implicated in various steps of tumor progression and the development of metastasis. TGF-β has an active role in platelet aggregation, regulation of megakaryocyte activity, and activity of the VEGF system [Table 1].[22]
Table 1: Summary of studies on thrombocytosis in gynecological cancers

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 > Thrombocytosis in Carcinoma Ovary Top


Thrombocytosis is more common in carcinoma ovary as compared to benign tumors.[44] In different studies, the prevalence of thrombocytosis ranges from 7% to 43%.[6],[23],[32] Crasta et al. revealed that patients with preoperative thrombocytosis were found to have lower hemoglobin (P < 0.0002), advanced stage (P < 0.05), and higher grade tumors (P < 0.02).[23] Zeimet et al. investigated 130 women with epithelial ovarian tumors and found that thrombocytosis was associated with advanced stage disease, higher serum levels of CA 125, ascites, and greater chance of suboptimal cytoreduction.[6]

Menczer et al. carried out a similar retrospective study in a cohort of seventy patients with invasive epithelial ovarian carcinoma and reported a higher incidence of thrombocytosis in women with advanced stage disease and significantly shorter periods of survival.[24] Other studies also found that thrombocytosis was significantly correlated with advanced stage and higher grade epithelial ovarian tumors, lymph node metastases, greater volume of ascites, and less optimal tumor cytoreduction with significantly shorter disease-free and overall survival.[25],[26]


 > Thrombocytosis in Endometrium Carcinoma Top


Preoperative thrombocytosis is an independent prognostic factor in Stage III and IV endometrial cancer was studied by Scholz et al. They reported that 5 years disease-free survival and overall survival were influenced significantly by FIGO stage, thrombocytosis, and cervical involvement.[33]

Gorelick et al. evaluated the role of preoperative thrombocytosis and its association with survival in a predominantly African-American and Caribbean-American urban population. Fourteen (18.2%) of 77 patients exhibited thrombocytosis. The median overall survival in patients without thrombocytosis was 24.0 ± 4.5 months (n = 21) and in patients with thrombocytosis was 7.0 ± 3.8 months (n = 8, P= 0.015). Data indicated that preoperative thrombocytosis among high-risk inner-city patients with Stages III to IV endometrial cancer is an independent prognostic indicator.[34] In a recent study, Gu et al. showed that the prevalence of thrombocytosis increases with stage. Furthermore, patients with thrombocytosis died at a younger age as compared to those with normal platelet count (64.3 years and 74.5 years, respectively).[37]


 > Thrombocytosis in Cervical Cancer Top


Thrombocytosis has been suggested to be a poor prognostic indicator in patients with cervical cancer. In a retrospective study by De Jonge et al., cumulative survival rate for the 93 patients with normal platelet counts was 65% whereas it was 25% for the twenty with thrombocytosis.[38]

Lopes et al. reviewed pretreatment platelet counts of 643 women treated for cervical cancer between 1983 and 1992 and correlated to each patient's age, stage of disease, histologic type, node status (when available), and outcome. The 5-year survival rate for patients with thrombocytosis was 57.1%, which was significantly worse than the 76.5% for those with normal platelet counts (P < 0.01). Thrombocytosis was not found to be an independent prognostic factor in patients with carcinoma of the cervix in this study.[39]

Kawano et al. showed that thrombocytosis is associated with younger age (P = 0.0003), an advanced clinical stage (P < 0.0001), larger tumor (P = 0.0025), lower hemoglobin levels (P < 0.0001), and more frequent treatment failure (P = 0.0015).[40]


 > Thrombocytosis in Vulvar Carcinoma Top


Ofer et al. reviewed pretreatment platelet counts of 201 women treated for vulvar cancer and correlated to the patient's age, stage of disease, node status, histologic type, and outcome. Thrombocytosis was presented in 14.92% of patients with vulvar malignancies and in 15.46% of patients with squamous cell carcinoma of the vulva. No correlation was found between thrombocytosis and tumor size, incidence of lymph node metastases, or stage of the disease. The 5-year survival rate for patients with thrombocytosis was 89.29%, which was not significantly different from the 76.47% 5-year survival of patients with normal platelet counts (P = 0.586). When adjusted for age, histological differentiation, number of tumors, staging, incidence of nodal metastases, platelet count, hemoglobin, and white blood count, only the staging, number of tumors, and histological differentiation were associated with an unfavorable prognosis (P = 0.0001, P= 0.003, P= 0.03, respectively). Thrombocytosis was not found to be a prognostic factor in patients with carcinoma of the vulva in this series of 201 patients.[42]

A study by Hefler et al. in 62 patients, also demonstrated that pretreatment tumor anemia (hemoglobin < 12 g/dL) and elevated platelet count (>300,000/ÌL) were significantly associated with a poor overall survival.[7]


 > Results Top


The association of thrombocytosis with malignancies has been known for more than 100 years. Various studies have shown that thrombocytosis is associated with a poor prognosis in various gynecological. Carcinoma ovary with thrombocytosis is associated with suboptimal tumor resection, raised CA125 level. Thrombocytosis is common in advanced disease in patients with ovarian cancer, endometrial cancer, and cervical cancer. Therefore, it may be a marker of tumor burden or biologically more aggressive disease.


 > Conclusion Top


The prevalence of thrombocytosis associated with various cancers portrays a worse survival, independent of other clinical or biochemical factors. With further studies, this single independent prognostic factor may provide a simple approach to improved risk stratification of patients in future clinical trial protocols.

Acknowledgments

We acknowledge the help of our families, especially our little angels (Avishi and Saranya) for providing time and support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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