Leukemia & Lymphoma, October 2014; 55(10): 2391–2394 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.880430
Letter to the Editor
Potential utility of serum soluble LR11 as a diagnostic biomarker for intravascular large B-cell lymphoma Takeharu Kawaguchi1, Chikako Ohwada1, Masahiro Takeuchi1, Naomi Shimizu1, Emiko Sakaida1, Yusuke Takeda1, Shio Sakai1, Shokichi Tsukamoto1, Atsuko Yamazaki1, Yasumasa Sugita1, Morihiro Higashi2, Kazuhisa Fujikawa3, Kosei Matsue4, Koutaro Yokote5, Jun-Ichi Tamaru2, Hideaki Bujo6 & Chiaki Nakaseko1 1Department of Hematology, Chiba University Hospital, Chiba, Japan, 2Department of Pathology, Saitama Medical Center,
Saitama Medical University, Saitama, Japan, 3Department of Hematology, Chibaken Saiseikai Narashino Hospital, Chiba, Japan, 4Department of Hematology/Oncology, Kameda Medical Center, Chiba, Japan, 5Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan and 6Department of Clinical Laboratory and Medicine, Toho University Medical Center Sakura Hospital, Chiba, Japan
the time of disease remission in seven patients. Immunohistological staining with an antibody against LR11 (clone, A 2-2-3), and the measurement of serum sLR11 levels by a sandwich enzyme-linked immunosorbent assay (ELISA) method, were performed as previously reported [5]. Clinical and laboratory data were retrospectively collected. For comparisons of serum sLR11 levels between patients with IVLBCL and normal controls, serum samples were collected from 75 healthy adult volunteers, and for comparisons between IVLBCL and other hematological malignancies, serum samples of previously untreated patients with diffuse large B-cell lymphoma (DLBCL, n 53), FL (n 61) and AL (n 66) were collected. All patients and volunteers gave informed consent. Paired sample analyses of serum sLR11 levels at the time of diagnosis and upon remission were performed using the Wilcoxon’s signed-rank test. Comparisons of sLR11 levels in patients with IVLBCL with those in patients with other hematological malignancies were performed using Steel’s test. Multivariate analysis for factors associated with serum sLR11 levels was conducted using a linear regression model. For variable selection, the stepwise procedure was set to a threshold of 0.05 for inclusion or exclusion in the model. Tissue samples from patients with IVLBCL were obtained from the skin (n 5), bone marrow (n 2), lungs (n 2) and adrenal gland (n 1). The cytoplasm of IVLBCL cells, which were strongly positive for CD20, reacted specifically with anti-LR11 antibody, markedly highlighting the tumor cells [Figures 1(A)–1(F)]. Patient characteristics and serum sLR11 levels are shown in Table I. The median serum sLR11 level in patients with IVLBCL at the time of diagnosis was 86.0 ng/mL (mean standard deviation [SD], 385.3 702.1 ng/mL), which was significantly
Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of malignant lymphoma, characterized by selective growth of lymphoma cells within the vessel lumina in various organs [1]. The absence of typical clinical manifestations and the aggressive behavior of IVLBCL frequently make accurate and immediate diagnosis difficult. However, the recent development of rituximab-containing chemotherapy has improved the outcome of IVLBCL: a retrospective analysis of Western and Asian cohorts reported 3-year overall survival rates of 81% and 60%, respectively [2,3]. However, the diagnosis of IVLBCL in many patients still remains challenging. LR11 (also called SorLA or SORL1) is a type I membrane protein that releases serum soluble LR11 (sLR11) by proteolytic shedding. Although sLR11 was originally described as a biomarker for coronary stenosis [4], we recently reported that LR11 is expressed by several human leukemia cell lines, which release sLR11 into the culture medium. In addition, patients with acute leukemia (AL) showed significantly increased serum sLR11 levels compared to those in normal controls, which normalized upon disease remission [5]. Furthermore, LR11 was detected in follicular lymphoma (FL) cells, and serum sLR11 levels in patients with FL were significantly increased in association with greater tumor burden and the presence of bone marrow invasion, and normalized upon disease remission [6]. Considering the fact that 67% of patients develop bone marrow invasion [7], we evaluated the expression profile of LR11 in patients with IVLBCL. Tumor specimens and serum samples were collected from 10 patients with newly diagnosed and untreated IVLBCL at Chiba University Hospital and affiliated hospitals from 2009 to 2013. Informed consent was obtained from all patients. In addition, serum samples were collected at
Correspondence: Chikako Ohwada, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8677, Japan. Tel/fax: 81-43-225-6502. E-mail: chikako_ohwada@ faculty.chiba-u.jp Received 13 September 2013; revised 24 December 2013; accepted 30 December 2013
2391
2392 T. Kawaguchi et al.
Figure 1. Immunohistochemical staining for LR11 in IVLBCL. (A–C) Transbronchial lung biopsy (TBLB) (patient 4). (A) Hematoxylin–eosin (HE) staining (magnification 40), (B) CD20 staining (magnification 40), (C) LR11 staining (magnification 40). (D–F) Skin biopsy (patient 10). (D) HE staining (magnification 1000), (E) CD20 staining (magnification 1000), (F) LR11 staining (magnification 1000).
higher than that in healthy volunteers (median, 8.4 ng/mL; mean SD, 8.8 1.8 ng/mL; p 0.0001). Moreover, sLR11 levels in patients with IVLBCL were significantly higher than in those with DLBCL (median, 11.7 ng/mL; mean SD, 17.4 14.5 ng/mL; p 0.0001), FL (median, 14.5 ng/mL; mean SD, 19.4 17.1 ng/mL; p 0.0001) and AL (median, 22.8 ng/mL; mean SD, 43.1 63.4 ng/mL; p 0.0005). Furthermore, we identified 17 poor-risk patients among the DLBCL cohort according to the revised International Prognostic Index (R-IPI), and found that sLR11 levels in patients with IVLBCL were also significantly higher than those in poor-risk DLBCL (median, 17.8 ng/mL; mean SD, 25.3 21.1 ng/mL; p 0.0004, Figure 2). Receiver operating curve analysis established 28.3 ng/mL as a cut-off level with 100% sensitivity and 84.3% specificity for diagnosing IVLBCL among DLBCL, FL, AL and normal controls (n 265), with an area under the curve of 0.95. Paired sample analysis of seven patients showed that increased sLR11 levels at the time of disease diagnosis were significantly decreased upon disease remission (median, 86.0 ng/mL vs. 13.2 ng/mL; mean SD, 385.3 702.1 ng/mL vs. 13.1 3.7 ng/mL; p 0.0078). Multiple regression analysis showed that the serum lactate dehydrogenase (LDH) level was the only significant factor associated with serum sLR11 levels (R2 0.56, p 0.01), while no significant associations were observed for other clinical parameters such as sex, age, hemoglobin level, serum creatinine level, serum b2-microglobulin level and serum soluble interleukin-2 (IL-2) receptor level. Also, a patient with leukemic manifestation (patient 9 in Table I) showed an extremely high serum sLR11 level of 2295.0 ng/mL, which was the highest level in our entire patient series with hematological malignancies. LR11 is known to activate VLA-4 (very late antigen 4) through urokinase-type plasminogen activator receptor (uPAR)-mediated pathways, leading to macrophage adhesion and migration [8]. VLA-4 has an important role in B cell adhesion to endothelial and stromal cells and provides pro-survival signaling in lymphoma cells [9]. Furthermore,
VLA-4 is highly expressed by most primary lymphoma cells, including IVLBCL cells [10,11]. Previous reports suggested that IVLBCL cells lack CD29 (b1 integrin) or CD54 (intercellular adhesion molecule [ICAM]-1) expression, while others revealed that the characteristic expression pattern of CD11a (aL integrin) may contribute to the distinctive IVLBCL behavior [1,10,12]. Although the precise pathophysiology of IVLBCL is unknown, LR11 may further contribute to the vascular adhesion and intravascular proliferation of IVLBCL cells by uPAR-mediated activation of VLA-4. Furthermore, we have reported that LR11 can stabilize the bone marrow niche by regulating hypoxia-induced attachment of hematopoietic stem cells to bone marrow stromal cells through the uPAR-mediated signaling pathway [13]. Therefore, we speculate that LR11 may also play a role in bone marrow invasion by regulating the attachment of IVLBCL cells to bone marrow stromal cells. Although our series included a limited number of patients, we found a significant association between serum sLR11 and LDH levels. Also, a patient with leukemic manifestations showed an extremely high serum sLR11 level. These findings are compatible with our previous results found in FL and AL, that serum sLR11 levels are associated with tumor burden [6] and peripheral blast proportion [5]. Furthermore, sLR11 levels in patients with IVLBCL were significantly higher than those in DLBCL. The biological characteristics of IVLBCL are known to be coincident with those of DLBCL in many aspects, except for the tumor growth pattern in the lumina of vessels. Considering these findings, a high tumor burden, strong affinity for the bone marrow and a characteristic distribution of tumor cells within vascular vessels might be associated with the significantly increased serum sLR11 levels in patients with IVLBCL. Early and accurate diagnoses are extremely important in IVLBCL, because appropriate treatment has been shown to improve the clinical outcome [3]. Although recently developed diagnostic technology, such as random skin
2500 P = 0.0004 Serum sLR11 (ng/ml)
PS, performance status; CS, clinical stage (Ann Arbor); CNS, central nervous system; LDH, lactate dehydrogenase; Hb, hemoglobin; sCre, serum creatinine; b2-MG, b2-microglobulin; sIL-2R, serum soluble interleukin-2 receptor; sLR11, serum soluble LR11; CR, complete remission; NA, not available; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; HD-MTX, high-dose methotrexate; R-EPOCH, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide; PD, progressive disease.
R-CHOP HD-MTX R-CHOP R-CHOP NA NA NA 258.9 2295.0 60.3 7440 5562 2780 8.6 15.5 14.5 1.69 1.53 8.64 15.2 14.4 10.5 1265 2220 342 No Yes No IVA IVB IVB M F M
3 4 4 57 80 61 8 9 10
IVB IVB IVB IVB IVB M F F M M
4 1 4 4 4 72 66 72 76 73 3 4 5 6 7
*Biopsy-proven site.
R-CHOP HD-MTX R-CHOP HD-MTX R-CHOP HD-MTX R-EPOCH R-CHOP HD-MTX 9.4 13.2 20.5 14.3 11.6 96.1 31.7 221.1 75.9 28.3 25038 4902 6347 22 900 6886 9.3 2.7 7.2 7.2 4.5 0.81 0.53 1.08 1.4 0.7 450 723 934 604 185 No No No No No
7.9 11.4 7.9 7.9 7.4
CR PD CR
CR CR
CR CR CR CR CR
Outcome Treatment
R-CHOP HD-MTX R-CHOP HD-MTX 716.0 70.1 7304 7204 2.4 9.1 0.95 2.49 8.7 14.3 456 1327 No No M M
1 4 54 69 1 2
IVB IVA
Involved organs CNS, lung* CNS, adrenal gland, bone marrow, skin* CNS, bone marrow* Lung* Adrenal gland, skin* Bone marrow* Adrenal gland*, bone marrow Bone marrow, skin* Skin* Kidney, skin* CS Age Sex PS Patient no.
Table I. Patients’ characteristics.
Leukemic b2-MG sIL-2R sLR11 at diagnosis sLR11 at CR manifestation LDH (U/L) Hb (g/dL) sCre (mg/dL) (mg/dL) (U/mL) (ng/mL) (ng/mL)
13.3 9.6
Letter to the Editor 2393
2000 1500 1000 500 0
IVLBCL (N = 10)
Poor-risk DLBCL (N = 17)
Figure 2. Scatter plot of serum sLR11 levels in patients with IVLBCL and poor-risk DLBCL identified by R-IPI. Horizontal lines indicate median levels.
biopsies, has enabled the accurate diagnosis of IVLBCL [14], an immediate diagnosis is often challenging because tumor involvement can occur in any organ, even without apparent clinical signs. Hematological abnormalities and increased LDH levels commonly occur [3,15], but these manifestations are also common in other hematological diseases. Moreover, increased soluble interleukin-2 (IL-2) receptor levels have been reported in patients with IVLBCL [1], but a widely used specific serum biomarker that is directly derived from IVLBCL cells has not yet been identified. Furthermore, sLR11 levels are significantly higher in patients with IVLBCL than in those with other hematological malignancies. This finding may suggest that sLR11 levels can be used as an indicator of IVLBCL and help in making an accurate histological diagnosis. In addition, the significant reduction of sLR11 levels upon disease remission suggests that this protein may represent a sensitive marker for disease monitoring. In conclusion, LR11 is a novel molecule identified in IVLBCL, and considering the current paucity of functional biomarkers, serum sLR11 levels represent a potentially powerful diagnostic indicator for IVLBCL. Further investigations into LR11 mechanisms in IVLBCL may provide a better understanding of the pathophysiology of IVLBCL, and eventually might provide a novel therapeutic target. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Shimada K, Kinoshita T, Naoe T, et al. Presentation and management of intravascular large B-cell lymphoma. Lancet Oncol 2009;10:895–902. [2] Ferreri AJ, Dognini GP, Govi S, et al. Can rituximab change the usually dismal prognosis of patients with intravascular large B-cell lymphoma? J Clin Oncol 2008;26:5134–5136; author reply 5136–5137. [3] Shimada K, Matsue K, Yamamoto K, et al. Retrospective analysis of intravascular large B-cell lymphoma treated with rituximab-containing
2394 T. Kawaguchi et al. chemotherapy as reported by the IVL study group in Japan. J Clin Oncol 2008;26:3189–3195. [4] Takahashi M, Bujo H, Jiang M, et al. Enhanced circulating soluble LR11 in patients with coronary organic stenosis. Atherosclerosis 2010;210:581–584. [5] Sakai S, Nakaseko C, Takeuchi M, et al. Circulating soluble LR11/ SorLA levels are highly increased and ameliorated by chemotherapy in acute leukemias. Clin Chim Acta 2012;413:1542–1548. [6] Kawaguchi T, Ohwada C, Takeuchi M, et al. LR11: a novel biomarker identified in follicular lymphoma. Br J Haematol 2013;163:277–280. [7] Murase T, Yamaguchi M, Suzuki R, et al. Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. Blood 2007;109:478–485. [8] Ohwaki K, Bujo H, Jiang M, et al. A secreted soluble form of LR11, specifically expressed in intimal smooth muscle cells, accelerates formation of lipid-laden macrophages. Arterioscler Thromb Vasc Biol 2007;27:1050–1056. [9] Weekes CD, Kuszynski CA, Sharp JG. VLA-4 mediated adhesion to bone marrow stromal cells confers chemoresistance to adherent lymphoma cells. Leuk Lymphoma 2001;40:631–645.
[10] Kanda M, Suzumiya J, Ohshima K, et al. Intravascular large cell lymphoma: clinicopathological, immuno-histochemical and molecular genetic studies. Leuk Lymphoma 1999;34:569–580. [11] Mraz M, Zent CS, Church AK, et al. Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin alpha-4-beta-1 (VLA-4) with natalizumab can overcome this resistance. Br J Haematol 2011;155:53–64. [12] Kusaba T, Hatta T, Tanda S, et al. Histological analysis on adhesive molecules of renal intravascular large B cell lymphoma treated with CHOP chemotherapy and rituximab. Clin Nephrol 2006;65:222–226. [13] Nishii K, Nakaseko C, Jiang M, et al. The soluble form of LR11 protein is a regulator of hypoxia-induced, urokinase-type plasminogen activator receptor (uPAR)-mediated adhesion of immature hematological cells. J Biol Chem 2013;288:11877–11886. [14] Matsue K, Asada N, Odawara J, et al. Random skin biopsy and bone marrow biopsy for diagnosis of intravascular large B cell lymphoma. Ann Hematol 2011;90:417–421. [15] Ferreri AJ, Campo E, Seymour JF, et al. Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the ‘cutaneous variant’. Br J Haematol 2004;127:173–183.
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Letter to the Editor
Potential utility of serum soluble LR11 as a diagnostic biomarker for intravascular large B-cell lymphoma Takeharu Kawaguchi1, Chikako Ohwada1, Masahiro Takeuchi1, Naomi Shimizu1, Emiko Sakaida1, Yusuke Takeda1, Shio Sakai1, Shokichi Tsukamoto1, Atsuko Yamazaki1, Yasumasa Sugita1, Morihiro Higashi2, Kazuhisa Fujikawa3, Kosei Matsue4, Koutaro Yokote5, Jun-Ichi Tamaru2, Hideaki Bujo6 & Chiaki Nakaseko1 1Department of Hematology, Chiba University Hospital, Chiba, Japan, 2Department of Pathology, Saitama Medical Center,
Saitama Medical University, Saitama, Japan, 3Department of Hematology, Chibaken Saiseikai Narashino Hospital, Chiba, Japan, 4Department of Hematology/Oncology, Kameda Medical Center, Chiba, Japan, 5Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan and 6Department of Clinical Laboratory and Medicine, Toho University Medical Center Sakura Hospital, Chiba, Japan
the time of disease remission in seven patients. Immunohistological staining with an antibody against LR11 (clone, A 2-2-3), and the measurement of serum sLR11 levels by a sandwich enzyme-linked immunosorbent assay (ELISA) method, were performed as previously reported [5]. Clinical and laboratory data were retrospectively collected. For comparisons of serum sLR11 levels between patients with IVLBCL and normal controls, serum samples were collected from 75 healthy adult volunteers, and for comparisons between IVLBCL and other hematological malignancies, serum samples of previously untreated patients with diffuse large B-cell lymphoma (DLBCL, n 53), FL (n 61) and AL (n 66) were collected. All patients and volunteers gave informed consent. Paired sample analyses of serum sLR11 levels at the time of diagnosis and upon remission were performed using the Wilcoxon’s signed-rank test. Comparisons of sLR11 levels in patients with IVLBCL with those in patients with other hematological malignancies were performed using Steel’s test. Multivariate analysis for factors associated with serum sLR11 levels was conducted using a linear regression model. For variable selection, the stepwise procedure was set to a threshold of 0.05 for inclusion or exclusion in the model. Tissue samples from patients with IVLBCL were obtained from the skin (n 5), bone marrow (n 2), lungs (n 2) and adrenal gland (n 1). The cytoplasm of IVLBCL cells, which were strongly positive for CD20, reacted specifically with anti-LR11 antibody, markedly highlighting the tumor cells [Figures 1(A)–1(F)]. Patient characteristics and serum sLR11 levels are shown in Table I. The median serum sLR11 level in patients with IVLBCL at the time of diagnosis was 86.0 ng/mL (mean standard deviation [SD], 385.3 702.1 ng/mL), which was significantly
Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of malignant lymphoma, characterized by selective growth of lymphoma cells within the vessel lumina in various organs [1]. The absence of typical clinical manifestations and the aggressive behavior of IVLBCL frequently make accurate and immediate diagnosis difficult. However, the recent development of rituximab-containing chemotherapy has improved the outcome of IVLBCL: a retrospective analysis of Western and Asian cohorts reported 3-year overall survival rates of 81% and 60%, respectively [2,3]. However, the diagnosis of IVLBCL in many patients still remains challenging. LR11 (also called SorLA or SORL1) is a type I membrane protein that releases serum soluble LR11 (sLR11) by proteolytic shedding. Although sLR11 was originally described as a biomarker for coronary stenosis [4], we recently reported that LR11 is expressed by several human leukemia cell lines, which release sLR11 into the culture medium. In addition, patients with acute leukemia (AL) showed significantly increased serum sLR11 levels compared to those in normal controls, which normalized upon disease remission [5]. Furthermore, LR11 was detected in follicular lymphoma (FL) cells, and serum sLR11 levels in patients with FL were significantly increased in association with greater tumor burden and the presence of bone marrow invasion, and normalized upon disease remission [6]. Considering the fact that 67% of patients develop bone marrow invasion [7], we evaluated the expression profile of LR11 in patients with IVLBCL. Tumor specimens and serum samples were collected from 10 patients with newly diagnosed and untreated IVLBCL at Chiba University Hospital and affiliated hospitals from 2009 to 2013. Informed consent was obtained from all patients. In addition, serum samples were collected at
Correspondence: Chikako Ohwada, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8677, Japan. Tel/fax: 81-43-225-6502. E-mail: chikako_ohwada@ faculty.chiba-u.jp Received 13 September 2013; revised 24 December 2013; accepted 30 December 2013
2391
2392 T. Kawaguchi et al.
Figure 1. Immunohistochemical staining for LR11 in IVLBCL. (A–C) Transbronchial lung biopsy (TBLB) (patient 4). (A) Hematoxylin–eosin (HE) staining (magnification 40), (B) CD20 staining (magnification 40), (C) LR11 staining (magnification 40). (D–F) Skin biopsy (patient 10). (D) HE staining (magnification 1000), (E) CD20 staining (magnification 1000), (F) LR11 staining (magnification 1000).
higher than that in healthy volunteers (median, 8.4 ng/mL; mean SD, 8.8 1.8 ng/mL; p 0.0001). Moreover, sLR11 levels in patients with IVLBCL were significantly higher than in those with DLBCL (median, 11.7 ng/mL; mean SD, 17.4 14.5 ng/mL; p 0.0001), FL (median, 14.5 ng/mL; mean SD, 19.4 17.1 ng/mL; p 0.0001) and AL (median, 22.8 ng/mL; mean SD, 43.1 63.4 ng/mL; p 0.0005). Furthermore, we identified 17 poor-risk patients among the DLBCL cohort according to the revised International Prognostic Index (R-IPI), and found that sLR11 levels in patients with IVLBCL were also significantly higher than those in poor-risk DLBCL (median, 17.8 ng/mL; mean SD, 25.3 21.1 ng/mL; p 0.0004, Figure 2). Receiver operating curve analysis established 28.3 ng/mL as a cut-off level with 100% sensitivity and 84.3% specificity for diagnosing IVLBCL among DLBCL, FL, AL and normal controls (n 265), with an area under the curve of 0.95. Paired sample analysis of seven patients showed that increased sLR11 levels at the time of disease diagnosis were significantly decreased upon disease remission (median, 86.0 ng/mL vs. 13.2 ng/mL; mean SD, 385.3 702.1 ng/mL vs. 13.1 3.7 ng/mL; p 0.0078). Multiple regression analysis showed that the serum lactate dehydrogenase (LDH) level was the only significant factor associated with serum sLR11 levels (R2 0.56, p 0.01), while no significant associations were observed for other clinical parameters such as sex, age, hemoglobin level, serum creatinine level, serum b2-microglobulin level and serum soluble interleukin-2 (IL-2) receptor level. Also, a patient with leukemic manifestation (patient 9 in Table I) showed an extremely high serum sLR11 level of 2295.0 ng/mL, which was the highest level in our entire patient series with hematological malignancies. LR11 is known to activate VLA-4 (very late antigen 4) through urokinase-type plasminogen activator receptor (uPAR)-mediated pathways, leading to macrophage adhesion and migration [8]. VLA-4 has an important role in B cell adhesion to endothelial and stromal cells and provides pro-survival signaling in lymphoma cells [9]. Furthermore,
VLA-4 is highly expressed by most primary lymphoma cells, including IVLBCL cells [10,11]. Previous reports suggested that IVLBCL cells lack CD29 (b1 integrin) or CD54 (intercellular adhesion molecule [ICAM]-1) expression, while others revealed that the characteristic expression pattern of CD11a (aL integrin) may contribute to the distinctive IVLBCL behavior [1,10,12]. Although the precise pathophysiology of IVLBCL is unknown, LR11 may further contribute to the vascular adhesion and intravascular proliferation of IVLBCL cells by uPAR-mediated activation of VLA-4. Furthermore, we have reported that LR11 can stabilize the bone marrow niche by regulating hypoxia-induced attachment of hematopoietic stem cells to bone marrow stromal cells through the uPAR-mediated signaling pathway [13]. Therefore, we speculate that LR11 may also play a role in bone marrow invasion by regulating the attachment of IVLBCL cells to bone marrow stromal cells. Although our series included a limited number of patients, we found a significant association between serum sLR11 and LDH levels. Also, a patient with leukemic manifestations showed an extremely high serum sLR11 level. These findings are compatible with our previous results found in FL and AL, that serum sLR11 levels are associated with tumor burden [6] and peripheral blast proportion [5]. Furthermore, sLR11 levels in patients with IVLBCL were significantly higher than those in DLBCL. The biological characteristics of IVLBCL are known to be coincident with those of DLBCL in many aspects, except for the tumor growth pattern in the lumina of vessels. Considering these findings, a high tumor burden, strong affinity for the bone marrow and a characteristic distribution of tumor cells within vascular vessels might be associated with the significantly increased serum sLR11 levels in patients with IVLBCL. Early and accurate diagnoses are extremely important in IVLBCL, because appropriate treatment has been shown to improve the clinical outcome [3]. Although recently developed diagnostic technology, such as random skin
2500 P = 0.0004 Serum sLR11 (ng/ml)
PS, performance status; CS, clinical stage (Ann Arbor); CNS, central nervous system; LDH, lactate dehydrogenase; Hb, hemoglobin; sCre, serum creatinine; b2-MG, b2-microglobulin; sIL-2R, serum soluble interleukin-2 receptor; sLR11, serum soluble LR11; CR, complete remission; NA, not available; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; HD-MTX, high-dose methotrexate; R-EPOCH, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide; PD, progressive disease.
R-CHOP HD-MTX R-CHOP R-CHOP NA NA NA 258.9 2295.0 60.3 7440 5562 2780 8.6 15.5 14.5 1.69 1.53 8.64 15.2 14.4 10.5 1265 2220 342 No Yes No IVA IVB IVB M F M
3 4 4 57 80 61 8 9 10
IVB IVB IVB IVB IVB M F F M M
4 1 4 4 4 72 66 72 76 73 3 4 5 6 7
*Biopsy-proven site.
R-CHOP HD-MTX R-CHOP HD-MTX R-CHOP HD-MTX R-EPOCH R-CHOP HD-MTX 9.4 13.2 20.5 14.3 11.6 96.1 31.7 221.1 75.9 28.3 25038 4902 6347 22 900 6886 9.3 2.7 7.2 7.2 4.5 0.81 0.53 1.08 1.4 0.7 450 723 934 604 185 No No No No No
7.9 11.4 7.9 7.9 7.4
CR PD CR
CR CR
CR CR CR CR CR
Outcome Treatment
R-CHOP HD-MTX R-CHOP HD-MTX 716.0 70.1 7304 7204 2.4 9.1 0.95 2.49 8.7 14.3 456 1327 No No M M
1 4 54 69 1 2
IVB IVA
Involved organs CNS, lung* CNS, adrenal gland, bone marrow, skin* CNS, bone marrow* Lung* Adrenal gland, skin* Bone marrow* Adrenal gland*, bone marrow Bone marrow, skin* Skin* Kidney, skin* CS Age Sex PS Patient no.
Table I. Patients’ characteristics.
Leukemic b2-MG sIL-2R sLR11 at diagnosis sLR11 at CR manifestation LDH (U/L) Hb (g/dL) sCre (mg/dL) (mg/dL) (U/mL) (ng/mL) (ng/mL)
13.3 9.6
Letter to the Editor 2393
2000 1500 1000 500 0
IVLBCL (N = 10)
Poor-risk DLBCL (N = 17)
Figure 2. Scatter plot of serum sLR11 levels in patients with IVLBCL and poor-risk DLBCL identified by R-IPI. Horizontal lines indicate median levels.
biopsies, has enabled the accurate diagnosis of IVLBCL [14], an immediate diagnosis is often challenging because tumor involvement can occur in any organ, even without apparent clinical signs. Hematological abnormalities and increased LDH levels commonly occur [3,15], but these manifestations are also common in other hematological diseases. Moreover, increased soluble interleukin-2 (IL-2) receptor levels have been reported in patients with IVLBCL [1], but a widely used specific serum biomarker that is directly derived from IVLBCL cells has not yet been identified. Furthermore, sLR11 levels are significantly higher in patients with IVLBCL than in those with other hematological malignancies. This finding may suggest that sLR11 levels can be used as an indicator of IVLBCL and help in making an accurate histological diagnosis. In addition, the significant reduction of sLR11 levels upon disease remission suggests that this protein may represent a sensitive marker for disease monitoring. In conclusion, LR11 is a novel molecule identified in IVLBCL, and considering the current paucity of functional biomarkers, serum sLR11 levels represent a potentially powerful diagnostic indicator for IVLBCL. Further investigations into LR11 mechanisms in IVLBCL may provide a better understanding of the pathophysiology of IVLBCL, and eventually might provide a novel therapeutic target. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Shimada K, Kinoshita T, Naoe T, et al. Presentation and management of intravascular large B-cell lymphoma. Lancet Oncol 2009;10:895–902. [2] Ferreri AJ, Dognini GP, Govi S, et al. Can rituximab change the usually dismal prognosis of patients with intravascular large B-cell lymphoma? J Clin Oncol 2008;26:5134–5136; author reply 5136–5137. [3] Shimada K, Matsue K, Yamamoto K, et al. Retrospective analysis of intravascular large B-cell lymphoma treated with rituximab-containing
2394 T. Kawaguchi et al. chemotherapy as reported by the IVL study group in Japan. J Clin Oncol 2008;26:3189–3195. [4] Takahashi M, Bujo H, Jiang M, et al. Enhanced circulating soluble LR11 in patients with coronary organic stenosis. Atherosclerosis 2010;210:581–584. [5] Sakai S, Nakaseko C, Takeuchi M, et al. Circulating soluble LR11/ SorLA levels are highly increased and ameliorated by chemotherapy in acute leukemias. Clin Chim Acta 2012;413:1542–1548. [6] Kawaguchi T, Ohwada C, Takeuchi M, et al. LR11: a novel biomarker identified in follicular lymphoma. Br J Haematol 2013;163:277–280. [7] Murase T, Yamaguchi M, Suzuki R, et al. Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. Blood 2007;109:478–485. [8] Ohwaki K, Bujo H, Jiang M, et al. A secreted soluble form of LR11, specifically expressed in intimal smooth muscle cells, accelerates formation of lipid-laden macrophages. Arterioscler Thromb Vasc Biol 2007;27:1050–1056. [9] Weekes CD, Kuszynski CA, Sharp JG. VLA-4 mediated adhesion to bone marrow stromal cells confers chemoresistance to adherent lymphoma cells. Leuk Lymphoma 2001;40:631–645.
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