Pretreatment tumor-related leukocytosis misleads positron emission tomography-computed tomography during lymph node staging in gynecological malignancies

The accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) can be influenced by the increased glycolytic activity of inflammatory lesions. Here, using clinical data obtained from gynecological cancer patients, tumor samples and animal models, we investigate the impact of pretreatment tumor-related leukocytosis (TRL) on the diagnostic performance of 18F-FDG-PET/CT in detecting pelvic and paraaortic lymph node metastasis. We demonstrate that pretreatment TRL misleads 18F-FDG-PET/CT during lymph node staging in gynecological malignancies. In the mechanistic investigations, we show that the false-positive 18F-FDG-PET/CT result for detecting nodal metastasis can be reproduced in animal models of TRL-positive cancer bearing G-CSF expressing cervical cancer cells. We also show that increased 18F-FDG uptake in non-metastatic nodes can be explained by the MDSC-mediated premetastatic niche formation in which proinflammatory factors, such as S100A8 or S100A9, are abundantly expressed. Together, our results suggest that the MDSC-mediated premetastatic niche created in the lymph node of TRL-positive patients misleads 18F-FDG-PET/CT for detecting nodal metastasis.


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Antibodies used A total of 551 gynecological cancer patients who had undergone a preoperative 18F-FDG-PET/CT scan before initial staging surgery at Osaka University Hospital were included in the current study. Because the samples were chronologically divided into two cohorts (the primary cohort (n=426); treated between April 2007 and December 2014, the validation cohort (n=125); treated from January 2015 to October 2018), the sample size for each cohort has not been determined.
In human clinical data analyses, patients with coexisting hematologic malignancies, administration of corticosteroids or recombinant G-CSF, or acute or chronic infection were excluded, as these factors can be a cause of leukocytosis or a false-positive detection of lymph node metastasis by 18F-FDG-PET/CT.
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ME180 human cervical cancer cell line and Ishikawa human endometrial cancer cell line were perchased from the American Type Culture Collection.
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All procedures involving mice and rats, and their care were approved by the Institutional Animal Care and Use Committee of the Osaka University in accordance with the relevant institutional and NIH guidelines.
A total of 551 Japanese women with gynecological cancer who underwent pretreatment 18F-FDG-PET/CT scans were included (Detailed clinicopathological characteristics were described in Table 1 and Supplementary Table 2. Patients with newly diagnosed gynecological cancers who had undergone a preoperative 18F-FDG-PET/CT scan before initial staging surgery at Osaka University Hospital (primary cohort, from April 2007 to December 2014; validation cohort, from January 2015 to October 2018) are included in the current study. We cannot exclude potential sources of bias: self-selection bias might have been introduced by the physicians when they perform 18F-FDG-PET/CT scan. As patients who had not undergone 18F-FDG-PET/CT scan were not included in this study, this might have led to over-or under-estimation of the results.
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