To the Editor: We read with interest the article by Bogos et al. (1), which showed that circulating lymphatic/vascular endothelial progenitor cells (LVEPC) are significantly increased in small cell lung cancer (SCLC) patients and correlate with clinical behavior. We wish to comment on several unconvincing issues regarding the methodology and patient characteristics presented in the study.

Circulating LVEPC are an extremely rare cell population in peripheral blood that may contribute to lymphangiogenesis and/or angiogenesis and may be phenotypically identified by combining markers CD34, CD133, and vascular endothelial growth factor receptor 3 (VEGFR3). Unfortunately, the quantification of LVEPC reported by Bogos et al. is confusing. Here, authors recovered a mononuclear cell fraction after erythrocyte lysis (instead of the expected whole leucocyte fraction) to measure LVEPC as CD34+VEGFR3+ events using a two-color fluorescence-activated cell sorting method in which neither the blood volume nor the number of events accumulated for fluorescence-activated cell sorting analysis was specified. Bogos et al. show what they consider to be a typical analysis (Fig. 1A) in which LVEPC represented 95% of total CD34+ cells, but where morphologic characteristics, isotypic controls, and the gating strategy are cruelly lacking. Moreover, Salven et al. (2) initially reported LVEPC levels in healthy adults of 0.2 ± 0.1% of CD34+ cells, representing approximately 5 LVEPC/mL of blood (based on a mean value of 2,500 CD34+ cells/mL). Here, authors report a median value of 1,625 LVEPC/mL in SCLC patients, which is not only inconsistent with those values reported by Salven et al. but also appears highly improbable in light of the fact that LVEPC, like VEGFR2+ circulating endothelial progenitor cells, represent a tiny fraction of circulating CD34+ cells (3, 4).

Moreover, the prognostic value of LVEPC levels in the SCLC patient group analyzed in this study is very questionable. First, multivariate analysis included neither performance status (a major prognostic factor) nor achievement of a complete response (5). Also, no information on the sequence of radiotherapy and chemotherapy was provided although the time to thoracic radiotherapy has been recently highlighted as a potential factor of treatment efficacy. Finally, the overall survival reported may have been affected by the absence of prophylactic cranial irradiation, which is a standard treatment in responding patients.

Finally, Bogos et al. proposed that LVEPC could be surrogate markers to monitor the efficacy of antiangiogenic therapies in SCLC. Although it is likely that circulating endothelial progenitor cells and LVEPC will become biomarkers in cancer, the authors have omitted that there is currently limited data supporting the clinical interest of such agents in SCLC.

No potential conflicts of interest were disclosed.

1
Bogos
K
,
Renyi-Vamos
F
,
Dobos
J
, et al
. 
High VEGFR-3-positive circulating lymphatic/vascular endothelial progenitor cell level is associated with poor prognosis in human small cell lung cancer
.
Clin Cancer Res
2009
;
15
:
1741
6
.
2
Salven
P
,
Mustjoki
S
,
Alitalo
R
,
Rafii
S
. 
VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells
.
Blood
2003
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3
Khan
SS
,
Solomon
MA
,
McCoy
JP
 Jr
. 
Detection of circulating endothelial cells and endothelial progenitor cells by flow cytometry
.
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2005
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4
Peichev
M
,
Naiyer
AJ
,
Pereira
D
, et al
. 
Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors
.
Blood
2000
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952
8
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5
Paesmans
M
,
Sculier
JP
,
Lecomte
J
, et al
. 
Prognostic factors for patients with small cell lung carcinoma: analysis of a series of 763 patients included in 4 consecutive prospective trials with a minimum follow-up of 5 years
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