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� � ����������Vol. 36, pp. 405�415, 2008

3q27�BCL6 ���������� ������������������

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� �9:;<=>?@AB��CDE�F��EG�BH+@�I>( 3q27�BCL6 <=HJKAB��CDLM 10�NO�PQ���RST��UPVW9:;�XY!Z[H\]�(�^_!WE`�H^�ab>cd��) ��CDO�EPQe( fghPij��hPN 1�2kEf�;HJl( O�V>e��HJ�ij.mnO� �centroblast� Nop�) �U�qPVe CD3�( CD19( CD20( CD56�( CD34� grsN( CD5 W CD10 >e�B�WtB�gop�) ��RSTeDLBCL �9��W FL �1��Nop�) D�O�e( 3q27�BCL6 9:;<=H .mNuv�@g( �URSw>?@ Hans E�xy�z{H!j@WGCB �germinal center B-cell�F �6��W non-GCBF �4��g|}~( "���GCBFNei�p�) �^����xNo@ IPI �international prognostic index� E���(}N�#Nop�) O�WRSTe����j��W��( 9:;�XY!<=>?��FH���@�WeG�No@g( �^����$H�%w�@�We�&No@W���~@)

����AB��CD( BCL6( 3q27<=( �^_!( �^��

���D�Ne( ��E��o@je�F>�Zbi9:;<=g'��~�j@) 2001 �>(��~� WHO ��e( ��bi9:;<=HJK��B)��H�*���FW�@E>��( ��CDe�+s���RSTN����j@1� 2�)

��CDe B�T�NKO�B>���~( �� BO�>,+�@-�B��CD �FL� E t�14;18��q32;q21.3�(  ¡¢£¤��CDE t�8;14��q24;q32�(��¤xO���CD �MCL� E t�11;14��q13;q32�g¥�b9:;<=No@) BO���CDe( ��>¦�@�U§¨©�� �Ig� XY!E V�D�J ª«�W .mNE¬­®®¯£°ª«�E±>( 9:;<=Huv�@3� 4�) t�14;18�W t�11;14�e��(3q27�BCL6 <=W t�8;14� e .mN²#@�Wg�~}NE³´>?�.��>�~�j@) �E<=>?@ BCL6 µ)Ve( .mN(q� BO�

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����������������� ��3q27�BCL6 ���� ����� Ig ���������������� ����� B ��� ����������!� �"#$%&%'�(��)!*+,-���� B &%'� �di#use large B cell lymphoma: DLBCL� ����&%'�!�./01� 2��������1�)��2����/3��4.� �������� !�"5#6����������$! 3q27�BCL6 ���7�&%'�%&�8'9� (:;��<)�=> 10*+!:,?-�@.94�

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/0�� 20061 9A3/ 20081 8A�2B&C%DEF�GHI��34F!56�J79� 3q27�BCL6 ������@89�4 10*+!*�564.�9@94&%':!;K<=�L�9� MNO �Giemsa� ���''PQRS �Papani-colaou� ��!�����TU94� MNO���� L>94;K<=�VWXYZ!? 30@[A94� B 1ml �/9 1�1.5CMNO��I�D\9� E>94��I�FGH�]� 15�30 ���:� BI9^_J:TU945�� ''PQRS��� 95�`WXYZ! 30�[A9� 95�50�`WXYZaK�8L:� BI9� b���cBd$e&%��I! 3���94� 0.5�fgBMI!N�:BI9� 50�95�`WXYZaK!OB9� ������ OG100��I� EA100��I! 2���:� �P� QR� SL9^TU94���� !�� 9@hT�'�ij%UV9WX<=�L>9� hematoxylin & eosin �HE���!TU94� "5� ����k CD3� CD5� CD20�CD10k� �ventana��k BCL6k� �Novocastra��kMUM1k� �ABCAM��Yl� iRYm�dVd&Y�� nZ�GVoj`%�pqr[��s\t�u�d&Y!vw04�����'��x]1yz<^-_{�Yl

46�� 9@�1|�4&%':}`�abI�!c~-��X9��deI��4� RPMI1640 abI�Sef�Hg �FCS� � 15��z1y�D\9� de��� 37�C� 5�CO2 �%$��YWY! 24�48��ab94� abhi 2��j�� QZ���hkl� 0.02mg�ml �z1y�\��

���m��.4� �/� 2��ab:�� 1200�� 5��:�ng��^� 0.075M KCl �1|��� 15��opN��94� 1200�� 5��:�ng��^� qj�L�94�ZXC �Car-noy� [AI �VWXYZ 3 :rg 1�![A94� s�_Jt!<=�L>9� ����d&�e%N�: G �%�t�Yl4� ���uA�b)���� ���?�������b)��t �interna-tional system for human cytogenetic nomenclature:

ISCN�7� �v�4�Fluorescent in situ hybridization �FISH� ���

������1|e�DZ���&�d� BCL6�BCL2�IgH �RY� �LSI Dual Color, BreakApart Rearrangement Probe� �Yl48�� <-�z��� DNA � 70�C 70�"ZNC���2xSSC ! 2 ��w���]� xy�z!�RY�DNA � 37�C ! 16�18 �����{����]4�  ¡<¢94�RY���� ¡£|¤�!TU9� �����}c�@.94� <-�z���DNA��� ����'�Yl4�ZXC[A���Yl4� �ZXC[A94���~��0^lz3�4���� ��56�Yl4'�ij%[A<=�Yl4� 60�C ¥��!'�ij%�M894� $e¦%�`WXYZ!O'�ij%N�9� 0.2NHCl! 20��N�:� �R§CY¨K ! 37�C 10�20 �N�9� 10���"ZB&%©l!`WXYZ![A94� �_:��ZXC[A���u�� FISH 94�=ª«���¬­r�� ��®� 1395®���

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¯�@.94 3q27�BCL6 ��� �&%'� 10*+��@°��� Table 1 �±94� 1��42�71 ²!� LDH ��^��230IU�l� � 3 +��$�³! 7 +�n�9^l4� PS �Performancestatus�� 0� 5+ �*+ 1�2�3�7�8�� 1� 3+ �*+4�5�10�� 2 � 1 + �*+ 9�� 3 � 1 + �*+ 6�!*�4� :´���� �*+ 2�� � �*+ 5�� ���*+ 1�� µ� �*+ 6�!�./0 2+ �*+ 5�7�������^l4� J7�� �¶��~40^lz3�4*+ 6 �·�¸� <^-�G7t!*�R-�CHOP 7t�¹v94�J7j�(:�(�!�0¸� J7t����

\� � nº»¼� /406

20

���������� �� ����������������� �������� !"��#$%&'(�)�Working Formulation �WF��*+� REAL ,-� ./�01# WHO ,-�2001 2� ��+3��+� 0145���67�+3��+���89:;# IPI �interna-tional prognostic index�9� �� ��# WF �<=>?@ABCDEFEGH �NHL�I� CHOPJK+# CHOP -LMCNE�OJ�/�PQ�RS/�T3��� 2U ��60V��WX$Y �III�IV��performance status �PS� �2�4��Z[ LDH

��\]��^_$`� ��2�� 5����a)"���3�����Iab� low risk �0�1�� low-intermediate �2�� high-intermediate �3�� high risk�4�5� � 4cI,-��� ���89:;I IPI��+d� Low � 1 Q �PQ 8��Low-Inter-mediate �LI� � 4 Q �PQ 1�3�5�7��High-Inter-mediate �HI� � 4Q �PQ 2�4�9�10��High �H� �1Q �PQ 6��b�� e2� DNf(g CD20 gh� Rituximab �FiDjE���WXIkl���OJmn�o�/�� .�p�qr#shtu?v

wxy �CDC� zghtu?vw{1?vwxy�ADCC� d���+� FiDjE�klIa)FEGH�|}~OJ#� �� �� CHOP JK�3 R-CHOP JK�d`������� ���89:;I�`���!I"b�� R-CHOP JK�OJ/�PQ����a7���d/� R-IPI������+10�� R-IPI �#� Very good �0��Good �1�2�� Poor �3�4�5� � 3 cI,-���R-IPI ��+d very good � 1Q �PQ 8��good� 4Q �PQ 1�3�5�7��poor � 5Q �PQ 2�4�6�9�10��b�� �>?@FEGHI,-�� FL�# HI d H �PQ� 10�15�d�"7� IPI �#�,IOJ������"�b�� .��� FLI�/ FLIPI �follicular lymphoma internationalprognostic index�11� ������� ��#� 2U�61�����WX$Y �Ann Arbor ,- III�a�IVY���9���E �12 g�dl ����$`FEG^��� �5������LDH �\]������� 5��������+����89:;��DLBCL d FL �PQ��� 3q27�BCL6  ¡QI FLIPI��+d� Low �L�� 1Q �PQ 7��

Table 1. Clinical Features of B-cell Lymphoma Patients Associated with 3q27�BCL6 Translocations

3q27�BCL6  ¡�¢�>?FEGH 407

21

Intermediate �I�� 3� ��� 1�3�5��High �H�� 6� ��� 2�4�6�7�9�10������ �� 7�� IPI R-IPI ���� ������������FLIPI ������������� ����� R-CHOP ��� !"#�$%�&'!�FLIPI ! IPI�R-IPI �(�)*���+�

&��,�-.%���/012�� 3�45����45�� 67�389�:;<=>12 �centroblast� �Lennert� !�!12�� 12?��@A��B��� CCDEFGHI�3JK� LMNHI�12?�OP�Q�&'!� RSC/12�OP��TU�V��WX�

Fig. 1. Morphology of lymphoma cells.

Large sized lymphoid cells, twice larger than neutrophils, are seen. The

lymphoid cells have a round or irregular shaped nucleus with thick

membrane and condensed chromatin.

�a� Papanicolaous stain. �400�b� Giemsa stain. �400

Fig. 2. Histology of 3q27�BCL6 translocation.A di#use proliferation of medium to large-sized cells with vesicular chromatin

and prominent nucleolus is seen. The lymphoma cells are positive for BCL-6

�c� and MUM-1 �d�, but negative for CD10 �d� by immunohistochemistry. Eachof BCL-6 and MUN-1 exhibits unclear positive staining in some lymphoma

cells. a �400; b,c,d �200

YZ [ \]^_` %408

22

��� �Fig. 1�� ����� DLBCL 9 ��FL 1� ���� �Table 1������������ �FCM� �� CD3��CD

19��CD20��CD56��CD34� ���������� CD10 � 5 �� 2�5�7�9�10��� � 5 �� 1�3�4�6�8��! ����� "#$%&'�� CD10 � �� 7 ( 1 )(*+�,�- BCL6 � ����� Hans (./0�1213, 14�)3�45� GCB 6 6� 7 GCB 6 4���� �Fig. 3, Table 2�� FL�8-9:;�18q21.3�BCL2 <=)>?@A� BCL2 BC� ��4(�D�� 3q27�BCL6 <=(EF�"#GH�I4 BCL6 BCJ(� KLM��� N(N5�� OPQRS)�-� DNA�RNA�TUB

C(�,�)VW��M�IXYZ[S5��(\]�^UP4_` )ab���4�CD5 � 6( 1�� ����� CD5 � T@A�� 5c4� de B @Afg�-h �ij Ck��li�/@A�ijf�de novoCD5�DLBCL �� 5c41� 2�� de novo CD5�

DLBCL (mnopq�� ;r�s tu�vwx�B �y�LDH (z{�|}�~)pq5��IPI �;���415�18�� ����i(���IX R-CHOP ����o��5cX� N� ��������(U�'oYZ[S��^c�cX� ��� CD5 (�U�'oYZ��[S5������4�GH������ 1 �� 10��������

Table 2. Immunohistochemistry of B-cell Lymphoma Patients with 3q27�BCL6Translocations

Fig. 3. Decision tree for TMA classification of DLBCL by Hans.

3q27�BCL6 <=)>?� �ijf 409

23

�� 1 � ��� 1�������� �� ������ �� 6 ���� 35�57 ������near-diploidy� �� ��� �� 6 ������87��������� !� �Table 3�� ISCN�� "#�����$%&'�()*+,-� ./012)345�6'78)9:�;<=- 6�� >?>� @ABC���$%&')�DEFG��H!� IJ�� ISCN )K<LMNOA��PQH! 1RS��3 Table 3 )�T� I-=������UV �Spectral karyotyping: SKY�8�

� FISHUV�WX> YZ>� �Fig. 5�� 3� ��� 2�3�9�� t�3;14��q27;q32�� 14q32�IgH� 1� ��� 5�� t�3;22��q27;q11.2� � 22q11�IgL �� ��[\ ��� 7�8�� Ig ]^_`a�bc�� t�3;3��q27;q29� � t�3;5��q27;q13� �� �� 1� ��� 7��� 3q27�BCL6 );<� FL )de�H 18q21.3�BCL2 bc3f(� �Table 3�����GV);<ghijklRS�BmnoApqrs�X!� FISH)7\�t 10��� 3q27�BCL6 bc�uvJ��wf>�� ���GV�f(=-� 18q21.3�BCL2 bc 1 � ��� 7��

FISH �3xbc�uvJ��wf>y�� FISH�� 5� ��� 2�3�4�7�9�� 14q32�IgHbc�f(=-� z 5� ��� 1�5�6�8�10�� 14q32�IgH `a�bc�� �� 3q27�BCL6 bc{|�}~�����N�@A�� z�I-`a����'J��wf,-�19�25��

� �

3q27�BCL6bc�� FL 15�� DLBCL 20�30��f(=-'�������\� B RS@ABC)��'�� �40��2���' DLBCL H?��3����!1� 2��@ABC���&'RS�� �����?=���RS���RS����RS �immunoblast� )��,-'5� 12�� ���RS����������\� �)������-��=-'� MN��A��R���� ��� !�¡¢�� �������1 H!>�£f(=->L>L��)¤> !'�RS¥�¦§¨/�� ©)ªS�=-'� ��RS�� ����)��-�uvRS��'� ���«����� ��¬­®�MN��A�¯!°±�

Table 3. Molecular Cytogenetic Analysis of B-cell Lymphoma Patients Associated with 3q27�BCL6 Translocations

;² ³ ´µ¶·¸ =410

24

���������� ��� � 1�2������������� ��������� !"#$%�� 3q27�BCL6 &'#()*�� +,��-.����#()�/0��12� DLBCL�� FL �34����/��#567892:;<� WHO =>��� FL �?@AB�CD��/��E�/0���FG� grading#HI� �J���/0��� 0�5# Grade 1� 6�15# Grade

2� 16KL# Grade 3E%�� Grade 3a ��/���M6%�NG�� �/���O��29NG#3b �=>%�� PQ���,R���/0���;<<4� 3q27�BCL6 &'#()?@���Grade 3 ��SE�TUV�<�� S�W*�Grade 1 �;<� ��XEABY�Z[7<\]�� ��X�^��_�#`a729��b7� ABcd��_�#ef7I�<4Egh��<� S�W*�� ij�=k�lm���no�pqr?���s2:;<SE:�� ?@"��/0���t.�u?@"��/���56789<vw"xgh����

W* 7� 3q27�BCL6�yh� 18q21.3�BCL2&'xz;89<� 18q21.3�BCL2 &'�{|�CD�V�D�J }~�� 3q27�BCL6 &'���/�CD��������}~�������SE����89�1�4�� �;8� 18q21.3�BCL2 #()pqr?���=�7� ��/�CD��������}~����V�� 3q27�BCL6 &'#��7<x�EZ�V��26� 27�� �ij������m�?@���,R��9��#��78x� -.��m#��%�E����������87�ISE�TUV��� WHO=>��ij�&'� �98 "{|"¡¢£#=>%�� ¡¢£�?@���{|�ij��m#��7{|�¤y%���b7� {|�ij�&'#��7<pqr?���� ��/�V��¥�¦�&'#��7I�SE�§¨V���S��� {|"¡¢£E�2©E)�DNA���ªij�&'# «�pqr?�£�#¬­%�SE#§789�� ,REij�������E�®¯�� °±V��t.*�^²789�³´���

Fig. 4. Representative G-banded karyotype of t�3;5��q27;q13� and t�14;18��q32;q11.2�.The arrows indicate abnormal chromosomes. BCL 6, BCL 2, and IGH are located on

chromosome 3q27, 18q21.3 and 14q32, respectively.

3q27�BCL6 &'#()µ"pqr? 411

25

�������� IPI�R-IPI�FLIPI ��� ������ �������������������� ����� !�"#$%&'(��������)� *+�,-������./�012*�� 3��45 6789:6;7 2<=>�sIL-2R��p53�BCL2 ?@�BCL6 AB�CDE*�FG�� HI� IPI �JK���� DLBCLL��� cDNA M6N:OP6�QR�ST B�GCB� U�V W B-like �ABC� U�XYZ �type3� �[�*��13�� XYZ�\]�^_�`���ABCU�a.�� 3�bcd+GCBU� ABCU�ef���g�h�0ij*��� .d.�cDNA M6N:OP6�k[�� RNA �l����mn�obp>Cq��hR� .d�rs�hRt3�uv��w_x�yz�{|���d}�� QR~���$w_�����30C�����(�{|���C12*�� Tissue microar-ray �TMA� 0�����.� CD10�BCL6�MUM1 �Q� Hans �O�����C��*��14�� GCB U� CD10� 0 CD10��BCL6��

MUM1� � Non-GCB U� CD10��BCL6��MUM1� 0 CD10��BCL6��MUM1� C��� ������ST� 3q27�BCL6 ����l����� Hans �O���������)� �fFGCB U0��30C��*��� .d.� GCBU� 6 ��� GCB UC 4 ��F��� 3��� cDNA M6N:OP60 TMA �QR[�*�� GCB U0� GCB U�� ��������������������4� Ch�� ���������C�:9 6¡¢¡�9�ef£�4� �h�C� ���¤¥�7¦���C[W��§¤.�STd+¨�[W����AB��©¦897C GCB Ud+� GCB Uª0«W.�4� C¬z+���

� �

��>���­®.���¯Q°��±²��³.F��C� �����]´�h}�� ���,-�������� 3q27�BCL6 ���¤¥L��µW.������¶���q�ChR� �����

Fig. 5. FISH results of splitting probes of BCL6 and BCL2.

�a� Split signals of BCL6. Arrows indicate splitted signals of BCL6 probe. Arrow head isnormal BCL6.

�b� Interface cell showed fusion signals of IGH-BCL2. Arrows indicate normal BCL2 andIGH. Arrow heads indicate fusion signals of IGH-BCL2.

�c� Fusion signals show BCL2 BCL6. Split signal of red �IGH� and green �BCL2�.

·¸ � Y¹º»¼ +412

26

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3q27�BCL6 fghij��� !" 413

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Abstract

Clinicopathological Features of Lymphoma Associated with 3q27�BCL6Translocations Based on Cytology, Histology, Immunology,

and Molecular Cytogenetics

Yo Kato1, Tasuku Saito1, Kohei Ogawa1, Yasuyuki Inoue1, Masayuki Kato1,

Yasushi Shibuya1, Yoshinori Suzuki1, Shigeki Kosugi1, Michiko Irei1,

Takao Suzuki1, Aki Kyo1, Masatomo Takahashi1, Junki Koike2,

Naoya Nakamura3, and Ikuo Miura1

Ten lymphoma patients associated with 3q27�BCL6 translocations were investigated retrospectively bycytology, histology, cytogenetics, and fluorescence in situ hybridization �FISH�, to explore a possibleclassification by chromosomal translocations. Common cytological features were centroblasts without

cytoplasmic granules. Typical immunological phenotype by flow cytometry and immunohistochemistry

was CD3��CD19��CD20��CD56��CD34� with variable CD5 and CD10 positivity. Pathological diag-noses were nine of di#use large B cell lymphoma �DLBCL� and one of follicular lymphoma �FL�.Immunohistochemistry disclosed germinal center B-cell like �GCB� subtype �6 cases� and non-GCB subtype�4 cases� according to algorithm by Hans. Risk groups by IPI �international prognostic index� were variousand it was assumed to be caused by additional chromosomal changes to 3q27�BCL6 translocations. Themalignalt lymphoma may be classified into subtype having various prognoses by chromosome transloca-

tions.

1 Division of Hematology and Oncology, Department of Internal Medicine, St. Marianna University School ofMedicine

2 Department of Diagnostic Pathology, St. Marianna University School of Medicine3 Department of Pathology, Tokai university School of Medicine

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