Biologic correlates of 18F-FDG uptake on PET in pulmonary pleomorphic carcinoma

doi:10.1016/j.lungcan.2010.05.021

Lung Cancer

Volume 71, Issue 2, February 2011, Pages 144-150

https://doi.org/10.1016/j.lungcan.2010.05.021 Get rights and content

Abstract

Background

Pulmonary pleomorphic carcinoma is a rare epithelial tumor, and little is also known about the information on the usefulness of 2-[¹⁸F]-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) positron emission tomography (PET). Therefore, we conducted the study including the underlying biologic analysis of ¹⁸F-FDG uptake.

Methods

Fifteen patients with pulmonary pleomorphic carcinoma who underwent ¹⁸F-FDG PET before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (Glut1); glucose transporter 3 (Glut3); hypoxia-inducible factor-1 alpha (HIF-1α); cell proliferation (Ki-67 labeling index); vascular endothelial growth factor (VEGF); microvessels (CD34); cell cycle control marker (p53); and apoptosis marker (bcl-2). These parameters were correlated with a control group of patients with other non-small cell lung cancer (NSCLC) (n = 33).

Results

The maximal standardized uptake value (SUV_max) of the primary tumors in 15 patients ranged from 6.1 to 26.8 (median 19.3). There were positive correlation between ¹⁸F-FDG uptake and Glut1 (p = 0.0016), Glut3 (p = 0.0080), VEGF (p = 0.0048), and microvessel density (MVD) (p = 0.0005). HIF-1α, p53 and bcl-2 showed no positive correlation with ¹⁸F-FDG uptake. ¹⁸F-FDG uptake, Glut1, Glut3, HIF-1α, VEGF and Ki-67 were significantly higher in patients with pulmonary pleomorphic carcinoma than those with other NSCLC.

Conclusion

¹⁸F-FDG uptake in pulmonary pleomorphic carcinoma is closely associated with the presence of glucose metabolism (Glut1 and Glut3) and angiogenesis (VEGF and MVD). The relationship between ¹⁸F-FDG uptake and these biomarkers may lead to a more rational use of PET scan in pulmonary pleomorphic carcinoma.

Introduction

Pulmonary pleomorphic carcinoma is rare and its incidence has ranged from 0.1% to 0.4% of all lung cancer [1]. The recent World Health Organization (WHO) histologic classification of lung tumors lists five subtypes of sarcomatoid carcinoma: pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma [2]. Pleomorphic carcinoma is defined as a carcinoma consisting of spindle and giant cells alone or a carcinoma with a sarcomatoid tumor component of at least 10% [2], [3], [4]. Pulmonary pleomorphic carcinoma has a more aggressive clinical course than other non-small cell lung cancer (NSCLC), and the response to systemic chemotherapy is generally poor [3], [4], [5]. Recent studies indicated that 2-[¹⁸F]-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) uptake within the primary tumor of pulmonary pleomorphic carcinoma was higher than other NSCLC [6]. However, little is known about the relationship between ¹⁸F-FDG uptake and pulmonary pleomorphic carcinoma.

The usefulness of ¹⁸F-FDG positron emission tomography (PET) for cancer diagnosis has been investigated in many studies [7], [8], [9]. Determination of malignant lesions with ¹⁸F-FDG PET is based on the glucose metabolism [10], [11]. The overexpression of glucose transporter 1 (Glut1) has been shown to be closely related to ¹⁸F-FDG uptake in human cancer [10], [11]. However, little is known about the pathogenesis and the mechanism of ¹⁸F-FDG uptake in pulmonary pleomorphic carcinoma. Glut1 is thought to be a possible intrinsic marker of hypoxia, and the expression of Glut1 has been found to be regulated by hypoxia in a hypoxia-inducible factor (HIF)-1-dependent way [12], [13]. Previous studies suggest that hypoxic conditions correspond to a higher ¹⁸F-FDG uptake [14], [15]. In addition, several researchers described the relationship between ¹⁸F-FDG uptake and the expression of vascular endothelial growth factor (VEGF) or microvessel density (MVD) [16], [17]. HIF-1α is considered to support tumor growth by the induction of angiogenesis via the expression of the VEGF and also by high and anaerobic metabolic mechanisms [18]. As many factors can influence the extent of ¹⁸F-FDG uptake, the underlying mechanisms for ¹⁸F-FDG accumulation are still a matter of debate in various human neoplasms. However, there is still no data about the underlying biologic mechanisms of ¹⁸F-FDG uptake in pulmonary pleomorphic carcinoma. Therefore, we conducted the study to investigate the biological correlation of ¹⁸F-FDG on PET in pulmonary pleomorphic carcinoma. In the present study, we examined the correlation between ¹⁸F-FDG uptake and immunohistochemical markers of glucose metabolism, tumor hypoxia, angiogenesis, cell cycle control and apoptosis. As a control group of patients with other lung cancer, we also evaluated the biological correlation of ¹⁸F-FDG on PET in NSCLC.

Section snippets

Patients

Between March 2004 and October 2008, we retrospectively analyzed 17 consecutive pulmonary pleomorphic carcinomas (0.8%) from a total of 2083 primary lung cancers at Shizuoka Cancer Center. Pleomorphic carcinoma was diagnosed according to the 2004 WHO classification [2]. A diagnosis was obtained based on the light microscopic findings and it was confirmed based on immunohistochemical examinations. Pleomorphic carcinoma was defined as NSCLC containing at least 10% sarcomatoid components. All

Patient characteristics

Patient's characteristics are listed in Table 1. The median age of the patients was 72 years (range, 47–81 years). Twelve patients were men and three were women. Performance status (PS) was 0–1 in all patients. Twelve patients were smokers, and there were eight patients with stage I–II and seven patients with stage III–IV. Eight of 15 patients were diagnosed by resected primary tumor. Of the other seven patients, six patients were diagnosed by bronchoscopic biopsy, and one by surgical biopsy.

Discussion

This is the first study to evaluate the biological correlation of ¹⁸F-FDG uptake on PET in pulmonary pleomorphic carcinoma. There was statistically significant relationship between ¹⁸F-FDG activity and the expression of Glut1, Glut3, VEGF and CD34. Especially, the expression of Glut1 and VEGF was closely correlated with ¹⁸F-FDG uptake. However, there was no statistically significant relationship between ¹⁸F-FDG uptake, and Ki-67, p53 and bcl-2. As compared with other NSCLC, ¹⁸F-FDG uptake,

Conflict of interest statement

We, all authors, have no financial or personal relationships with other people or organizations that could inappropriately influence our work.

Acknowledgements

This work was supported in part by Grant 21790793 (K.K.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and National Hospital Organization Policy Based Medical Services.

We thank all staffs of pathology department in Shizuoka Cancer Center for their technical assistance of immunohistochemical analysis.

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We found a high standardized fluorodeoxyglucose uptake (maximum standardized uptake value) of 19.25 ± 16.69 in PSC, which was roughly similar to previous results.28,29 These studies28,29 also showed significantly higher positron emission tomography uptake in PSC compared with NSCLC. This study had several limitations.
Pulmonary sarcomatoid carcinoma (PSC) is a rare type of lung cancer. This study aimed to explore the appropriate treatment for PSC.
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PPC contains carcinomatous and sarcomatoid components and is classified as a subtype of sarcomatoid carcinoma of the lung in the World Health Organization histologic classification of lung neoplasms [2,3]. It has been reported that PPC has more aggressive malignant potential than any other non–small cell lung cancer (NSCLC) and is closely linked to a worse prognosis and poorer response to systemic chemotherapy [4-6]. Because of its rarity, little is known about useful biomarkers to predict the outcome of treatment in patients with PPC.
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Biologic correlates of 18F-FDG uptake on PET in pulmonary pleomorphic carcinoma

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Patients

Patient characteristics

Discussion

Conflict of interest statement

Acknowledgements

Lung Cancer

Lung Cancer

Eur J Cancer

Biochem Biophys Res Commun

Lung Cancer

J Biol Chem

J Thorac Cardiovasc Surg

Pathology and genetics of tumours of the lung, pleura, thymus and heart

Pleomorphic (spindle/giant cell) carcinoma of the lung. A clinicopathologic correlation of 78 cases

Cancer

Pulmonary carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements: a clinicopathologic and immunohistochemical study of 78 cases

Am J Surg Pathol

Pleomorphic carcinoma of the lung: clinicopathologic characteristics of 70 cases

Am J Surg Pathol

Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients

J Clin Oncol

Dose fluorine-18 fluorodeoxyglucose metabolic imaging of tumor benefit oncology?

Eur J Nucl Med

The use of FDG-PET in differentiating infectious from malignant central nervous system lesions in patients with AIDS

J Nucl Med

Correlation of Glut-1 glucose transporter expression with [18F] FDG uptake in non-small cell lung cancer

Eur J Nucl Med

Biologic correlates of ¹⁸F-FDG uptake on PET in pulmonary pleomorphic carcinoma

Correlation of Glut-1 glucose transporter expression with [¹⁸F] FDG uptake in non-small cell lung cancer