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 a –c , 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.