3 | DISCUSSION
Production of G-CSF by cancer cells was first reported in 1977 by Asano et al.17 In that report, the diagnostic criteria for G-CSF-producing cancer were as follows: (a ) abnormally high WBC count in the peripheral blood with no evidence of infection; (b ) abnormally high serum G-CSF level; (c ) decrease in the WBC count or G-CSF level after cancer treatment; and (d ) G-CSF expression in tumor tissues. The authenticity of criterion d is controversial because studies indicate that the sensitivity for this criterion is not high (i.e., approximately 70%)18,19. Based on criteria ac , a literature search using PubMed with the search terms “uterine cervical cancer ” AND “granulocyte colony stimulating factor ”, followed by full-manuscript examination, identified only 14 cases of G-CSF-producing UCC reported to date (Table 2 ). The median age of patients was 64 years, and the histopathological type was squamous cell carcinoma in 64% of the cases. These patient demographics were in line with those reported for UCC in general20,21. Seventy-five percent of the patients exhibited elevated serum CRP levels before the initial treatment. Seventy-five percent of the patients experienced local recurrence or distant metastasis within 6 months after the initial treatment, suggesting resistance to conventional treatment and poor prognosis. The present case had a stage-IIB tumor with PALN involvement and expired 5 months after completion of chemoradiotherapy because of multiple distant metastases. Previous studies show that the 5 year overall survival rate of cohorts predominantly composed of PALN-positive stage-IIB tumors treated with chemoradiotherapy is approximately 40–60%22,23, highlighting the aggressive behavior of the tumor in the present case.
The mutational landscape of G-CSF-producing cancer remains unclear. A small number of studies have analyzed a few genes of interest in G-CSF-producing lung cancers. Pre-clinical studies identified inactivating mutations in TP53 andRASSF1A 24, and reported conflicting results on the presence of activating mutations inKRAS 24,25, whereas activating mutations inEGFR were identified in a clinical tumor26. To the best of our knowledge, this is the first study reporting the mutation profiles of G-CSF-producing cancer using a clinically available sequencing panel containing hundreds of genes. In the present case, the mutation spectrum in a three-base context was not typical for UCC15. None of the mutations in PIK3C2B ,KDR , and TET2 identified in the present case were reported in two previous large-scale landmark studies of UCC-mutation profiles27,28. By contrast, mutations in genes such asPIK3CA , PTEN , STK11 , KRAS , ARID1A ,EP300 , and FBXW7 , which were recurrently identified in previous landmark studies, were absent in the present case. Taken together, these data suggest that G-CSF-producing UCC is genetically distinct from other UCCs. Further compilation of clinical sequencing data is needed to elucidate the mutational landscape of G-CSF-producing cancer.
G-CSF-producing UCCs show resistance to conventional treatment (Table 2 ). Therefore, treatment strategies specific for this type of cancer need to be established. One candidate strategy is the use of molecular targeted drugs selected based on actionable mutation profiles. PIK3C2B and KDR encode class II phosphoinositide-3-kinase isoform C2β and vascular endothelial growth factor receptor 2, respectively. Therefore, cases such as the present case, which harbor somatic mutations in these genes, could be treated with inhibitors of the relevant PI3K/AKT/mTOR pathway29,30. Another candidate strategy is carbon ion radiotherapy. Patients with stage-IIB and -IIIB disease treated with carbon ion radiotherapy survived 108 and 30 months, respectively, with no evidence of recurrence11. The efficacy of the precision medicine approach and that of carbon ion radiotherapy for G-CSF-producing UCCs should be further investigated.
As a limitation of this study, we were unable to assess the expression of G-CSF in the tumor tissue using immunohistochemistry because of insufficient sample material.