The prognostic significance of hypocholesterolemia in POEMS syndrome is being examined for the first time in this study. Cholesterol, as a highly reproducible, easy to detect, and affordable laboratory indicator, may be a reliable candidate indicator for predicting the prognosis of POEMS syndrome, even though the molecular mechanisms that link cholesterol to cancer remain elusive.

Cholesterol is known to play an important role in the maintenance of cell membranes and the regulation of membrane fluidity and function, including transmembrane signaling and cell adhesion to the extracellular matrix. It is also known that cancer cell proliferation is dependent on either the de novo synthesis of cholesterol in the endoplasmic reticulum or the uptake of cholesterol from the bloodstream through receptor-mediated endocytosis of low-density lipoproteins (LDL) [16]. Tumor cells preferentially meet their high cholesterol requirements by increasing endogenous cholesterol synthesis through upregulation of HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) and increased expression of the LDL receptor [17, 18]. Therefore, a low serum TC level may be a sign of tumor progression. Previous epidemiologic studies have also shown that low serum cholesterol levels are associated with higher cancer incidence and higher cancer-related mortality. This could be explained by the relationship between the immune system and cholesterol metabolism. There are several reports that a low serum TC level is associated with an impaired immune system. Men with hypocholesterolemia have been found to have significantly fewer circulating lymphocytes, T cells and CD8 cells than men with hypercholesterolemia [19]. Bensinger et al. reported that cellular accumulation of cholesterol is essential for the activation and proliferation of CD4þ T cells [20]. Cholesterol binds directly to the a-chain of the T cell receptor and thus regulates nanoclustering and activation of the receptor. In addition, T cell activation triggers a simultaneous suppression of the liver X receptor pathway for cholesterol transport and an induction of the sterol regulatory element- binding protein pathway for cholesterol synthesis. However, even after T cell activation, T cell proliferation is prevented if cholesterol accumulation is not achieved. Therefore, persistently low serum cholesterol levels may impair cell-mediated immunity and lead to immune escape and cancer progression. Thus, low serum cholesterol might be associated with tumor development or progression.

Hypocholesterolemia was found in hematological tumors. Kuliszkiewicz-Janus et al. discovered a simultaneous reduction in TC, HDL-C and LDL-C concentrations during disease activity of acute leukemia and non-Hodgkin's lymphoma (NHL) [21]. Gao et al. identified the lipid profiles in CLL and diffuse large B-cell lymphoma (DLBCL), which manifested as reduced concentrations of TC, HDL-C and LDL-C [10, 13]. Yavasoglu et al. also discovered that newly diagnosed CLL and multiple myeloma (MM) patients had significantly lower TC, HDL-C and LDL-C levels [9, 14]. Our results supported the previously mentioned finding that the majority of patients with POEMS syndrome had lower TC, HDL-C and LDL-C levels. An inverse relationship between HDL-C and NHL was also observed by Lim et al. according to which the risk of NHL decreased by 15% with every 5 mg/dL increase in HDL-C level [12]. Shor et al. also discovered that the risk of hematological malignancy decreased by 2.4% for every 1 mg/dL increase in LDL-C levels [22].

Our study discovered that lower TC levels at diagnosis were correlated with poorer PFS and OS in patients with POEMS syndrome, and at the same time, low TC in the serum was an independent risk factor for both PFS and OS. In line with our findings on tumor prognosis, Parsa N et al. showed in a prospective cohort study that a low serum cholesterol level was significantly correlated with a higher risk of overall cancer mortality [23]. In DLBCL patients, Gao et al. showed that TC was linked to poor PFS and OS [13]. Additionally, CLL patients with hypocholesterolemia also had a worse time to first treatment (TTFT) and cancer-specific survival (CSS) [10]. Serum cholesterol has therefore been proposed as a prognostic indicator for POEMS syndrome. We believe that it is a good idea for patients with POEMS syndrome to undergo serum lipid testing on initial admission, which can be easily performed in all hospitals, including community hospitals. Special attention should be paid to patients with low TC because of their potentially worse disease outcomes.

Patients with concomitant low TC levels had poorer OS in the high-risk group compared with those with normal TC levels, but there was no discernible difference in the low- or intermediate-risk groups. We speculated that decreased TC levels may serve as a predictive factor for mortality in patients in the high-risk group, as it may further identify the high-risk patients in the high-risk group. However, it would be inappropriate to directly use our results as a new criterion for risk stratification of patients because we need larger data to re-examine our results and validate them in different centers.

The cut-off value for TC constructed from the ROC curves was slightly lower than 3 mmol/L in this study for the following possible reasons. First, the level of TC may vary according to ethical or geographical differences [24]. Second, 3 mmol/L is the lower limit of the normal range for a healthy population, and our cut-off value was derived from patients with POEMS syndrome who had relatively low TC levels. Thus, further large cohort studies and external validation studies should be conducted to determine the exact serum TC concentration that has the highest prognostic value in patients with POEMS syndrome.

The present study was subject to several limitations. First, it was a retrospective study at a single center with a single participant and a small sample size, which may lead to selection and sampling bias. Even if we control the balance for measured factors with a strict statistical correction, there may be unmeasured confounders, such as nutritional status, chronic liver disease, and critical illness status, which are also associated with low TC. Second, the wide range of diagnosis timing might lead to large heterogeneity. Third, our analysis is based on retrospective data from the Asian population, which may also limit the generalizability of our findings. Larger clinical studies, especially prospective studies, are required to further define the prognostic impact of lowered TC levels in individuals with POEMS syndrome.

In summary, patients with POEMS syndrome who had a low serum TC concentration were more likely to have an unfavorable outcome. A low TC level could allow further identification of high-risk cases in the high-risk group and thus improve risk stratification for POEMS syndrome. Given that lipid levels could be easily monitored and are reproducible, a low TC level might be an ideal prognostic marker for future clinical practice in POEMS syndrome.