To the best of our knowledge, this study was the first to confirm the relationship between G-CSF-producing lung cancer and PD-L1 expression. G-CSF-producing lung cancer is associated with high fever, increased inflammatory response, and increased WBC count. It progresses rapidly and is associated with an extremely poor prognosis.

The diagnostic criteria for G-CSF-producing malignant tumor are as follows: (1) marked increase in WBC count without infection or other diseases, (2) increased serum G-CSF levels, (3) reduction in WBC count after tumor resection, and (4) G-CSF-positive staining of tumor tissues on IHC [5]. On the contrary, as immunostaining for G-CSF was not available in our hospital, this study was only performed in patients with increased serum G-CSF levels due to G-CSF-producing lung cancer. Between 2009 and 2019, 13 patients had increased serum levels of G-CSF that could be immunostained for PD-L1. As shown in Table 3, the PD-L1 TPSs were ≥50%, 1%–49%, and <1% in 9 (69.2%), 1 (7.7%), and 3 (23.1%) patients, respectively. This result is clearly higher than the percentage of patients in previous studies with a PD-L1 TPS of ≥50% (30%) [6, 7]. Although this study included a small number of participants, PD-L1 expression is highly likely upregulated in those with G-CSF-producing lung cancers.

Several studies reporting the abnormal accumulation of G-CSF-producing tumors in the bone marrow examined on FDG-PET are available, which is considered useful for diagnosis [8,9,10,11]. In the present study, 12 of 13 patients with G-CSF-producing lung cancers showed diffuse accumulation of FDG in the bone marrow, and all 4 patients with a confirmed diagnosis of G-CSF-producing lung cancer showed FDG accumulation. As previously reported, FDG accumulation in the bone marrow is useful in differentiating patients with this disease.

Treatment of advanced-stage lung cancer has dramatically changed since the discovery of the EGFR gene mutation in the 2000s and various driver gene mutations [12,13,14]. Furthermore, nivolumab, a programmed death-1 antibody, was approved for use in December 2015 in Japan; multiple ICIs, including pembrolizumab, have also been approved [6, 15,16,17]. As regards the therapeutic effect of ICIs, pembrolizumab used as first-line treatment had a response rate of 33.3% and a disease control rate of 50%, whereas two patients using nivolumab as second-line treatment had PD. The PD-L1 TPS was ≥50% in all patients who received pembrolizumab as first-line treatment but was lower than the response rate reported in the KEYNOTE-024 trial. Although this finding is ambiguous owing to the small number of cases, the underlying mechanisms involved in the occurrence of resistance to some ICIs may contribute to the development of G-CSF-producing lung cancer.

This study showed that ICIs are a useful treatment option for G-CSF-producing lung cancer, although their efficacy is limited. In patients with G-CSF-producing lung cancers, the ECOG-PS often decreases due to high fever and increased inflammation. Hence, the disease must be diagnosed as early as possible and chemotherapy plus ICI or ICI combinations should be used as treatment instead of ICI alone to achieve greater efficacy. Therefore, early diagnosis is important for maintaining good ECOG-PS. The current diagnostic criteria for G-CSF-producing tumors are not useful for selecting the appropriate treatment for rapidly progressing G-CSF-producing lung cancer. This is because many institutions, including our hospital, use G-CSF levels and results of immunostaining to assess for G-CSF as criteria, which do not provide immediate results. In the case that led to this study, the WBC count was normal at the time of diagnosis; however, fever, increased inflammatory response, PET-CT findings, and high G-CSF count led to the suspicion of G-CSF-producing lung cancer. In this case, leukocytes increased to 10,000 at the start of treatment; in response to pembrolizumab treatment, the serum G-CSF level, which was 180 pg/mL prior to the start of treatment, decreased below the measured sensitivity (19.5 pg/mL) after the initiation of treatment. In other words, depending on the progression status, patients with G-CSF-producing lung cancers may not necessarily have high WBC levels. However, as mentioned earlier, PET-CT findings are useful for differentiating G-CSF-producing lung cancers. Therefore, we hypothesized that the presence of diffuse bone marrow accumulation on PET-CT, high WBC count, increased inflammatory response (increased C-reactive protein), and fever should be considered for diagnosing G-CSF-producing tumors.

This study has some limitations. First, it was a small, uncontrolled, single-center study with no comparison groups. Second, the G-CSF level was measured at the discretion of the attending physician, and not all patients with suspected G-CSF-producing lung cancer were tested. Third, immunostaining for G-CSF was not performed; hence, it was possible that the reliable G-CSF-producing tumors were not collected. The reason for this is that the conditions for immunostaining of G-CSF were not available at our hospital owing to the lack of insurance coverage. Fourth, this study enrolled patients who were diagnosed with this disease in 2009–2019, and data of the oldest specimen from the 13 patients were finally extracted in 2012; those from 2012 had a PD-L1 TPS of 95%, while all seven patients from 2018 and later had a TPS of 50% or higher. However, only two of the six specimens from 2017 and earlier had a TPS of 50% or higher. This finding suggests that the older specimens may have had inferior staining and may have had lower PD-L1 expression than they actually did. Finally, it remained unclear whether the production of G-CSF by the tumor reduced the effect of ICI. IL-6 levels may be increased in G-CSF-producing tumors [11]. The IL-6 levels were measured in two patients in our hospital, and both patients showed increased levels. Neither of these two patients showed positive response to pembrolizumab treatment. In addition, IL-6 is one of the causes of ICI resistance [18]. The co-expression of G-CSF and IL-6 possibly contributed to the occurrence of ICI resistance.