De novo diffuse large B-cell lymphoma with a CD20 immunohistochemistry-positive and flow cytometry-negative phenotype: Molecular mechanisms and correlation with rituximab sensitivity

Takashi Tokunaga, Akihiro Tomita, Keiki Sugimoto, Kazuyuki Shimada, Chisako Iriyama, Tatsuya Hirose, Mizuho Shirahata-Adachi, Yasuhiro Suzuki, Hiroki Mizuno, Hitoshi Kiyoi, Naoko Asano, Shigeo Nakamura, Tomohiro Kinoshita, Tomoki Naoe

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9 Citations (Scopus)

Abstract

CD20 is expressed in most B-cell lymphomas and is a critical molecular target of rituximab. Some B-cell lymphomas show aberrant CD20 expression, and rituximab use in these patients is controversial. Here we show both the molecular mechanisms and the clinical significance of de novo diffuse large B-cell lymphomas (DLBCL) that show a CD20 immunohistochemistry (IHC)-positive and flow cytometry (FCM)- negative (IHC[+]/FCM[-]) phenotype. Both IHC and FCM using anti-CD20 antibodies L26 and B1, respectively, were analyzed in 37 of the 106 cases of de novo DLBCL; 8 (22%) of these cases were CD79a(+)/CD20(+) with IHC and CD19(+)/CD20(-) with FCM. CD20 (MS4A1) mRNA expression was significantly lower in IHC(+)/FCM(-) cells than in IHC(+)/FCM(+) cells (P = 0.0005). No genetic mutations were detected in MS4A1 promoter and coding regions. Rituximab-mediated cytotoxicity in the CDC assay using IHC(+)/FCM(-) primary cells was significantly lower than in IHC(+)/FCM(+) cells (P < 0.05); however, partial effectiveness was confirmed. FCM using rituximab detected CD20 more efficiently than B1. No significant difference was observed between IHC(+)/FCM(-) and IHC(+)/FCM(+) patients in overall survival (P = 0.664). Thus, lower expression of CD20 mRNA is critical for the CD20 IHC(+)/FCM(-) phenotype. Lower CD20 expression with FCM does not rule out rituximab use in these patients if expression is confirmed with IHC. FCM using rituximab may be more informative than B1 for predicting rituximab effectiveness in IHC(+)/FCM(-) cases.

Original languageEnglish
Pages (from-to)35-43
Number of pages9
JournalCancer Science
Volume105
Issue number1
DOIs
Publication statusPublished - 01-01-2014
Externally publishedYes

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Lymphoma, Large B-Cell, Diffuse
Flow Cytometry
Immunohistochemistry
Phenotype
Rituximab
B-Cell Lymphoma
Messenger RNA
Centers for Disease Control and Prevention (U.S.)
Genetic Promoter Regions

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Tokunaga, Takashi ; Tomita, Akihiro ; Sugimoto, Keiki ; Shimada, Kazuyuki ; Iriyama, Chisako ; Hirose, Tatsuya ; Shirahata-Adachi, Mizuho ; Suzuki, Yasuhiro ; Mizuno, Hiroki ; Kiyoi, Hitoshi ; Asano, Naoko ; Nakamura, Shigeo ; Kinoshita, Tomohiro ; Naoe, Tomoki. / De novo diffuse large B-cell lymphoma with a CD20 immunohistochemistry-positive and flow cytometry-negative phenotype : Molecular mechanisms and correlation with rituximab sensitivity. In: Cancer Science. 2014 ; Vol. 105, No. 1. pp. 35-43.
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abstract = "CD20 is expressed in most B-cell lymphomas and is a critical molecular target of rituximab. Some B-cell lymphomas show aberrant CD20 expression, and rituximab use in these patients is controversial. Here we show both the molecular mechanisms and the clinical significance of de novo diffuse large B-cell lymphomas (DLBCL) that show a CD20 immunohistochemistry (IHC)-positive and flow cytometry (FCM)- negative (IHC[+]/FCM[-]) phenotype. Both IHC and FCM using anti-CD20 antibodies L26 and B1, respectively, were analyzed in 37 of the 106 cases of de novo DLBCL; 8 (22{\%}) of these cases were CD79a(+)/CD20(+) with IHC and CD19(+)/CD20(-) with FCM. CD20 (MS4A1) mRNA expression was significantly lower in IHC(+)/FCM(-) cells than in IHC(+)/FCM(+) cells (P = 0.0005). No genetic mutations were detected in MS4A1 promoter and coding regions. Rituximab-mediated cytotoxicity in the CDC assay using IHC(+)/FCM(-) primary cells was significantly lower than in IHC(+)/FCM(+) cells (P < 0.05); however, partial effectiveness was confirmed. FCM using rituximab detected CD20 more efficiently than B1. No significant difference was observed between IHC(+)/FCM(-) and IHC(+)/FCM(+) patients in overall survival (P = 0.664). Thus, lower expression of CD20 mRNA is critical for the CD20 IHC(+)/FCM(-) phenotype. Lower CD20 expression with FCM does not rule out rituximab use in these patients if expression is confirmed with IHC. FCM using rituximab may be more informative than B1 for predicting rituximab effectiveness in IHC(+)/FCM(-) cases.",
author = "Takashi Tokunaga and Akihiro Tomita and Keiki Sugimoto and Kazuyuki Shimada and Chisako Iriyama and Tatsuya Hirose and Mizuho Shirahata-Adachi and Yasuhiro Suzuki and Hiroki Mizuno and Hitoshi Kiyoi and Naoko Asano and Shigeo Nakamura and Tomohiro Kinoshita and Tomoki Naoe",
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Tokunaga, T, Tomita, A, Sugimoto, K, Shimada, K, Iriyama, C, Hirose, T, Shirahata-Adachi, M, Suzuki, Y, Mizuno, H, Kiyoi, H, Asano, N, Nakamura, S, Kinoshita, T & Naoe, T 2014, 'De novo diffuse large B-cell lymphoma with a CD20 immunohistochemistry-positive and flow cytometry-negative phenotype: Molecular mechanisms and correlation with rituximab sensitivity', Cancer Science, vol. 105, no. 1, pp. 35-43. https://doi.org/10.1111/cas.12307

De novo diffuse large B-cell lymphoma with a CD20 immunohistochemistry-positive and flow cytometry-negative phenotype : Molecular mechanisms and correlation with rituximab sensitivity. / Tokunaga, Takashi; Tomita, Akihiro; Sugimoto, Keiki; Shimada, Kazuyuki; Iriyama, Chisako; Hirose, Tatsuya; Shirahata-Adachi, Mizuho; Suzuki, Yasuhiro; Mizuno, Hiroki; Kiyoi, Hitoshi; Asano, Naoko; Nakamura, Shigeo; Kinoshita, Tomohiro; Naoe, Tomoki.

In: Cancer Science, Vol. 105, No. 1, 01.01.2014, p. 35-43.

Research output: Contribution to journalArticle

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T1 - De novo diffuse large B-cell lymphoma with a CD20 immunohistochemistry-positive and flow cytometry-negative phenotype

T2 - Molecular mechanisms and correlation with rituximab sensitivity

AU - Tokunaga, Takashi

AU - Tomita, Akihiro

AU - Sugimoto, Keiki

AU - Shimada, Kazuyuki

AU - Iriyama, Chisako

AU - Hirose, Tatsuya

AU - Shirahata-Adachi, Mizuho

AU - Suzuki, Yasuhiro

AU - Mizuno, Hiroki

AU - Kiyoi, Hitoshi

AU - Asano, Naoko

AU - Nakamura, Shigeo

AU - Kinoshita, Tomohiro

AU - Naoe, Tomoki

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N2 - CD20 is expressed in most B-cell lymphomas and is a critical molecular target of rituximab. Some B-cell lymphomas show aberrant CD20 expression, and rituximab use in these patients is controversial. Here we show both the molecular mechanisms and the clinical significance of de novo diffuse large B-cell lymphomas (DLBCL) that show a CD20 immunohistochemistry (IHC)-positive and flow cytometry (FCM)- negative (IHC[+]/FCM[-]) phenotype. Both IHC and FCM using anti-CD20 antibodies L26 and B1, respectively, were analyzed in 37 of the 106 cases of de novo DLBCL; 8 (22%) of these cases were CD79a(+)/CD20(+) with IHC and CD19(+)/CD20(-) with FCM. CD20 (MS4A1) mRNA expression was significantly lower in IHC(+)/FCM(-) cells than in IHC(+)/FCM(+) cells (P = 0.0005). No genetic mutations were detected in MS4A1 promoter and coding regions. Rituximab-mediated cytotoxicity in the CDC assay using IHC(+)/FCM(-) primary cells was significantly lower than in IHC(+)/FCM(+) cells (P < 0.05); however, partial effectiveness was confirmed. FCM using rituximab detected CD20 more efficiently than B1. No significant difference was observed between IHC(+)/FCM(-) and IHC(+)/FCM(+) patients in overall survival (P = 0.664). Thus, lower expression of CD20 mRNA is critical for the CD20 IHC(+)/FCM(-) phenotype. Lower CD20 expression with FCM does not rule out rituximab use in these patients if expression is confirmed with IHC. FCM using rituximab may be more informative than B1 for predicting rituximab effectiveness in IHC(+)/FCM(-) cases.

AB - CD20 is expressed in most B-cell lymphomas and is a critical molecular target of rituximab. Some B-cell lymphomas show aberrant CD20 expression, and rituximab use in these patients is controversial. Here we show both the molecular mechanisms and the clinical significance of de novo diffuse large B-cell lymphomas (DLBCL) that show a CD20 immunohistochemistry (IHC)-positive and flow cytometry (FCM)- negative (IHC[+]/FCM[-]) phenotype. Both IHC and FCM using anti-CD20 antibodies L26 and B1, respectively, were analyzed in 37 of the 106 cases of de novo DLBCL; 8 (22%) of these cases were CD79a(+)/CD20(+) with IHC and CD19(+)/CD20(-) with FCM. CD20 (MS4A1) mRNA expression was significantly lower in IHC(+)/FCM(-) cells than in IHC(+)/FCM(+) cells (P = 0.0005). No genetic mutations were detected in MS4A1 promoter and coding regions. Rituximab-mediated cytotoxicity in the CDC assay using IHC(+)/FCM(-) primary cells was significantly lower than in IHC(+)/FCM(+) cells (P < 0.05); however, partial effectiveness was confirmed. FCM using rituximab detected CD20 more efficiently than B1. No significant difference was observed between IHC(+)/FCM(-) and IHC(+)/FCM(+) patients in overall survival (P = 0.664). Thus, lower expression of CD20 mRNA is critical for the CD20 IHC(+)/FCM(-) phenotype. Lower CD20 expression with FCM does not rule out rituximab use in these patients if expression is confirmed with IHC. FCM using rituximab may be more informative than B1 for predicting rituximab effectiveness in IHC(+)/FCM(-) cases.

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