Differential Diagnosis of Cyclin D2+ Mantle Cell Lymphomas (MCL) Based on Combined FISH and Quantitative RT-PCR Analysis [1234]


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Differential Diagnosis of Cyclin D2+ Mantle Cell Lymphomas (MCL) Based on Combined FISH and Quantitative RT-PCR Analysis [1234]
Title of the conference
97th Annual Meeting of the United States and Canadian Academy of Pathology (USCAP)
Quintanilla-Martinez L., Koch I., Klier M., De Leval L., Klapper W., Siebert R., Fend F.
Denver, United States, 2008, March, 1-7
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Modern Pathology
Background: Mantle cell lymphoma (MCL) is characterized by the t(11;14)
chromosomal translocation, resulting in the overexpression of cyclin D1 (CycD1).
Recently, cases of MCL negative for cycD1 but positive for cycD2 or D3 were identified
by gene expression profiling and confirmed by immunohistochemistry (IHC). However,
no chromosomal aberrations were identified. The aim of this study is to present three
cases of cycD2+ MCL with a CCND2 translocation, and its differential diagnosis from
other low grade B-cell NHL based on IHC, RT-PCR and FISH analysis.
Design: Twenty cases of B-cell NHL (6 CLL, 6 MZL, 5 FL and 3 cycD2+ MCL) were
analyzed. IHC was performed with a polyclonal cycD2 antibody. CycD1, D2 and D3
mRNA levels were quantified by real-time RT-PCR in paraffin-embedded tissue. Nine
normal lymph nodes and 6 MCL cell lines (Granta, Jeko-1, Rec-1, Z-138, UPN-1 and
JVM-2) were used as controls. Interphase FISH with the CCND1, CCND2, IgH, Igκ
and Igλ probes was performed in the three MCL cases.
Results: FISH analysis in two of the three CycD1-MCL cases revealed an Igκ-CCND2
fusion, whereas case 3 showed an IgH-CCND2 translocation. IHC for cycD2 showed
strong positivity in all three MCL cases. Nevertheless, all other B-cell NHL were also
cyclin D2 positive, although with different intensities. The mean CycD2/TBP mRNA
ratio in normal lymph nodes was 6.8 (range 3.5 - 12.7), whereas all MCL cell lines,
with the exception of JVM-2 (CycD2/TBP ratio of 11.5) were cycD2 negative. In
contrast, cycD2 was highly expressed in the three cycD1-MCL cases (mean D2/TBP
ratio=213), clearly separated from CLL (mean D2/TBP ratio=26.6), FL (mean D2/TBP
ratio=20) and MZL (mean D2/TBP ratio=11.6). CycD1 mRNA was negative in all
cases. CycD3 mRNA levels were low to moderate in all NHL except for the 3 MCL
cases, which were negative. There was no correlation between the cycD2 staining and
mRNA expression.
Conclusions: In this study, we showed that true cycD2+MCL carry a translocation
involving CCND2 and either IgH or Igκ loci. As a result of this translocation cycD2
mRNA is highly overexpressed when compared with normal lymphoid tissue and
other B-cell NHL. In contrast, positive immunostaining for cycD2 is not specific for
a diagnosis of cycD2+MCL.
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