Hematopoietic Stem Cells
High number of circulating CD34+ cells in
patients with myelophthisis
Six patients with bone marrow micrometastases
from solid cancers presented with increased numbers
of circulating CD34+ cells; the CD34+ cell
counts were very high in some cases. By contrast,
no patient with metastatic cancer without bone
marrow involvement showed raised numbers of
circulating hemopoietic progenitors.
haematologica 2005; 90:976-977
(http:/

Ciancia R

Cosentini E

Martinelli V

Matano E

Petruzziello F

Picardi M

Rotoli B.

Six patients with bone marrow micrometastases from solid cancers presented with increased numbers of circulating CD34+ cells; the CD34+ cell counts were very high in some cases. By contrast, no patient with metastatic cancer without bone marrow involvement showed raised numbers of circulating hemopoietic progenitors

CIANCIA R.

COSENTINI E.

PICARDI, MARCO

PETRUZZIELLO F.

MATANO E.

ROTOLI B.

MARTINELLI, VINCENZO

Archivio della ricerca - Università degli studi di Napoli Federico II

High number of circulating CD34+ cells in patients with myelophthisis

ROTOLI, BRUNO

Letters to the Editor| 976 | haematologica/the hematology journal | 2005; 90(7)Hematopoietic Stem CellsHigh number of circulating CD34+ cells inpatients with myelophthisisSix patients with bone marrow micrometastasesfrom solid cancers presented with increased num-bers of circulating CD34+ cells; the CD34+ cellcounts were very high in some cases. By contrast,no patient with metastatic cancer without bonemarrow involvement showed raised numbers ofcirculating hemopoietic progenitors.haematologica 2005; 90:976-977(http://www.haematologica.org/journal/2005/7/976.html)The circulating CD34 (cCD34+) cell count is assesseddaily to monitor stem cell mobilization in patients under-going stem cell harvest from peripheral blood. Anothercondition with raised numbers of cCD34+ cells is  idio-pathic myelofibrosis,1 a finding suggesting that a normalbone marrow microenvironment is essential for the bind-ing of CD34+ cells to stroma. Myelophthisis is a peculiarbone marrow microenvironment alteration caused by thepresence of a high number of non-hematopoietic neo-plastic cells,  impairing hematopoiesis by largelyunknown mechanisms. Space occupation is not the mainmechanism, since micrometastases do not colonize thewhole marrow; rather, marrow is usually hypocellular,with some degree of fibrosis revealed at bone biopsy.2-3We investigated the number of cCD34+ cells in patientswith myelophthisis. We studied eleven patients with diffuse metastatic can-cer (Table 1). Myelophthisis was suspected in patients pre-senting uni-, bi-, or trilineage cytopenia not due tochemotherapy, and was documented by the finding of non-hematopoietic neoplastic cells in a bone marrow aspirateand/or biopsy. Peripheral blood, collected in K3EDTA, wasprocessed within 3 hours of venipuncture. CD34+ cellswere detected by a combination of two monoclonal anti-bodies, fluorescein isothiocyanate-conjugated anti-CD45and phycoerythrin-conjugated anti-CD34 (BectonDickinson, Boston, MA-USA); c-kit expression was alsomeasured. Fifty microliters of blood were incubated withthe antibodies for 20 min in tubes containing a knownnumber of microbeads. Cells were identified byFACSCalibur (Becton Dickinson, Boston, MA, USA)using scattering and fluorescence methods, and analyzedfollowing the sequential gating strategy recommendedby the International Society for Hematotherapy andGraft Engineering (ISHAGE). To exclude any  influence ofdrugs, patients were studied before or at least threemonths after chemotherapy; none of the patients hadreceived growth factors.Of the eleven patients with metastatic cancer of vari-ous origin, six showed bone marrow micrometastases,suggested by cytopenia and documented by bone aspi-rate and/or biopsy, while five patients had no sign ofbone marrow involvement. Marrow fibrosis (surroundingthe metastatic lesions) was detected in the three patientswith myelophthisis who underwent bone biopsy.cCD34+ (c-kit+) cell counts were elevated in all 6 patientswith myelophthisis, and were particularly high in  four..In contrast, CD34+ cells were almost undetectable in thepatients with metastatic cancer without bone marrowinvolvement (Table 1). The mean number of cCD34+ cellswas 49.2 and 1.2 cells/mL in the two groups, respectively.Among patients suffering from various types of disordersand tested for cCD34+ cells in our institution, the numberof cells detected was second highest in myelophthisis;the highest number was found in idiopathic myelofibro-sis (Figure 1).  Stem cell mobilization by growth factors and/orchemotherapy is caused by modifications of membrane-bound molecules that enable detachment of cells fromthe stroma. The only disease in which a high number ofcCD34+ cells has been described in the absence of anytreatment is idiopathic myelofibrosis;1,4,5 both an alteredbone marrow microenvironment and stem cell surfaceTable 1. Circulating CD34+cells in metastatic cancer patients with or without bone marrow involvement.Case Type of Blood countAge Gender cancer Hb g/dL WBC N Plt Cancer Previous CD34+ /mL¥109/L ¥109/L ¥109/L cells in therapybone marrow1 46 F Breast 8.2 4.400 2.200 63 yes None 60.62 34 M Lung 7.9 5.310 3.240 163 yes Cis-platinum 19.43 53 F Stomach 8.4 17.000 14.620 49 yes None 48.24 66 M Lung 7.7 14.600 10.366 24 yes None 149.45 53 M Stomach 8.2 3.040 1.824 70 yes None 8.16 50 F Breast 9.4 15.500 7.500 51 yes None 9.77 71 M Stomach 11.1 6.410 4.295 265 5-FU 08 64 M Lung 14.7 7.790 6.465 199 Taxotere 4.09 59 M Lung 13.4 9.920 6.448 191 Cis-platinum 2.010 77 M Colon 13.8 3.930 2.974 95* 5-FU 011 64 M Stomach 11.9 8.600 6.450 237 5-FU 0*: low count due to hypersplenism secondary to hepatitis C virus-related chronic hepatitis.haematologica/the hematology journal | 2005; 90(7) | 977 |Letters to the Editorabnormalities may underlie this phenomenon. A modestincrease of cCD34+ cells, attributed to granulocyte-mono-cyte colony-stimulating factor (GM-CSF) production bythe neoplastic tissue, has been described in patients withhead or neck cancer.6 We found that patients harboringcancer cells in the bone marrow had a mean of 49.2cCD34+ cells/mL, 50 times  more than in patients withmetastatic cancer without bone marrow involvement.This may be the consequence of various not mutuallyexclusive mechanisms, including: (i) a stromal alteration,evidenced in these patients by a frequent dry tap bonemarrow aspiration and some degree of fibrosis;2-3 (ii)growth factors with mobilizing properties producedlocally by the neoplastic cells; (iii) local production ofmolecules other than growth factors involved in stem cellmobilization. As far as concerns this last possibility, itcould be relevant to note that a cleaved molecule of sol-uble urokinase-type plasminogen activator (uPA) receptorseems to be involved in both the metastasizing capacityof cancer cells7 and in stem cell mobilization.8Our series is too small to draw any conclusion on apossible relation between degree of cytopenia and num-ber of cCD34+ cells; the type of primary tumor does notseem to be relevant. It is intriguing that two patients withraised cCD34+ cell counts had low hemoglobin andplatelet levels but elevated neutrophil counts, suggestinga common mechanisms for high cCD34+ and white cellcounts, as seen during mobilization. Several issues in thissetting need to be elucidated (e.g., cytokine levels inblood and bone marrow, pattern of adhesion moleculesand in vitro growth of cCD34+cells). From a clinical pointof view, our observations  suggest that high cCD34+ cellcount may be indicative of bone marrow involvement inpatients with metastatic cancer.Rosanna Ciancia, Vincenzo Martinelli, Elena Cosentini,Marco Picardi, Fara Petruzziello, Elide Matano, Bruno RotoliDivisions of Hematology,  Oncology and Trasfusional Medicine,Federico II University Medical School, Naples, ItalyFunding: Associazione Italiana contro le Leucemie (AIL), Salerno,ItalyAcknowledgments: the authors thank the pathologists Prof. GuidoPettinato and Dr. Giuseppe Ciancia for their valuable help in thestudy of bone marrow biopsies, and Dr Barbara Montante andDr. Ilaria Spagnoletti for their help in collecting the patients’ data.Key words: circulating CD34 positive cells, myelophthisis,metastatic cancer.Correspondence: Professor Bruno Rotoli, Divisione di Ematologia,Nuovo Policlinico, via S. Pansini 5, 80131, Naples, Italy.Phone: international +39.081.7462068. Fax: international+39.081.7462165. E-mail: rotoli@unina.itReferences1. Barosi G, Viarengo G, Pecci A, Rosti V, Piaggio G, MarchettiM, et al. Diagnostic and clinical relevance of number of circu-lating CD34+ cells in myelofibrosis with myeloid metaplasia.Blood 2001;98:3249-55. 2. Cotelingam JD. Bone marrow biopsy: interpretative guidelinesfor the surgical pathologist. Adv Anat Pathol 2003;10:8-26. 3. Bauermeister DE. Quantitation of bone marrow reticulin: anormal range. Am J Clin Pathol 1971;56:24-31. 4. Andreasson B, Swolin B, Kutti J. Patients with idiopathicmyelofibrosis show increased CD34+ cell concentrations inperipheral blood compared to patients with polycythaemiavera and essential thrombocythemia. Eur J Haematol 2002;68:189-93. 5. Passamonti F, Vanelli L, Malabarba L, Rumi E, Pungolino E,Malcovati L, et al. Clinical utility of the absolute number ofcirculating CD34-positive cells in patients with chronic myelo-proliferative disorders. Haematologica 2003;88:1123-9. 6. Pandit R, Lathers DM, Beal NM, Garrity T, Young MR. CD34+immune suppressive cells in the peripheral blood of patientswith head and neck cancer. Ann Otol Rhinol Laryngol 2000;109:749-54. 7. De Bock CE, Wang Y. Clinical significance of urokinase-typeplasminogen activator receptor (uPAR) expression in cancer.Med Res Rev 2004;24:13-39. 8. Selleri C, Montuori N, Visconte V, Carriero MV, Sidenius N,Serio B, et al. Involvement of the urokinase-type plasminogenactivator receptor in hematopoietic stem cell mobilization.Blood 2005;105:2198-205.Red Cell DisordersAssociation of the G-463A myeloperoxidasepolymorphism with infection in sickle cell anemiaInfections constitute a principal cause of morbid-ity and mortality in sickle cell anemia (SCA). Herewe present evidence to suggest that a polymor-phism (G-463A MPO) in the gene encoding themyeloperoxidase (MPO) enzyme, important for thehost defense system, may significantly increasesusceptibility to infection in SCA. haematologica 2005; 90:977-979(http://www.haematologica.org/journal/2005/7/977.html)Sickle cell anemia is characterized by morphologicallyabnormal red cells, vaso-occlusion with ischemic tissueinjury and susceptibility to infection. Infections, such aspneumonia, osteomyelitis, meningitis, urinary infectionsand septicemia, constitute a common cause of hospital-ization in patients. While many patients have reducedsplenic function, the mechanisms that render SCApatients more susceptible to infection are unclear. Theseverity of SCA varies greatly between individuals andthis phenotypic variability is generally attributed to so-called genetic modulators.1 Myeloperoxidase (MPO) is alysosomal enzyme found in neutrophils and monocytesFigure 1. Circulating CD34+ cells in patients with metastatic can-cer (with or without bone marrow involvement) or with varioustypes of myeloproliferative disorders. MF: idiopathic myelofibrosis;MPhth: myelophthisis; MetCa: patients with diffuse metastaticcancer without bone marrow involvement; ET: essential thrombo-cythemia; PV: polycythemia vera; Ph- MPD: Philadelphia negativemyeloproliferative disorders; ST: secondary thrombocytosis; N: 10healthy subjects; Mobilized N: normal subject mobilized by granu-locyte colony-stimulating factor for allogeneic donation; Solid line:upper limit in normal individuals.

High number of circulating CD34+ cells in patients with myelophthisis.

High number of circulating CD34+ cells in patients with myelophthisis.

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Archivio della ricerca - Università degli studi di Napoli Federico II

Archivio della ricerca - Università degli studi di Napoli Federico II