EGFR ˘ˇˆ˙˝˛˚˜ !# 1 - 聖マリアンナ医科大学...

Preview:

Citation preview

���� ����������Vol. 33, pp. 529�535, 2005

���������� EGFR ������������������ �!"# 1$

���

��

���

��1 �

��

��

�� 2 �

��

���

��

��1 �

��

���

���

���1

���

��

��1 �

��

������

1 � �

�!�

��"1 �

��

���

�#

��1

��

��$

���

��1

�%��

�&

3 !�'

�($

")&

#��1 �

��

���

�� 2

�$� :�% 17� 11& 21��

� �'�( 79)*+,* -.��/012�345* 6� + 7���2�8�9*:;,<

=>� ��2?@A,2!B*C:;=/"D5* EF*5D+ GHIJKL#$MNOP%&Q'()* �EBUS-GS� /$RST/UV45* +,WX�YZ(�[\>](^_+ -`_5WXab genomic DNA/cd4eHfghJKi�L*2jk.�lm/45>noEGFRk.�* exon212 missense mutation �L858R� /"D5* �/2(pqrstuvwx4+ y01za?2{1*|C/"D5* }~UV45 EBUS-GS *(��2ab��R34Z EGFR 0�*T�v�5>�b+ }�^`2(�/2����06^��n>v�7^_�*

��MNOP%&Q'()*+ �[\+ EGFR+ pqrstu

� �

�8�+9*�:](2(+ !�*U�ZMNO�����;]+ �MNO�ST<vV�_jR�* 4�4=��Z(+9*�>*�"2��v�b+ WX](@Z�`�R'����* n*a��'�2?4j+ n_@Z(+ ab� *��.P���ST¡¢.�STvV�_jR5* }~�_�_(+ GHIJKL#$MNOP%&Q'()*�EBUS-GS� /$R�n>2ab��2ab��R34Z+ �£¤��+9��ZST/UV¥�n>vZ�5*

^`2¦*� EGFR k.�* exon21 2 mis-

sense mutation �L858R� /"D+ pqrstuvwx45§�/�¨45*Z@©¥�*

� �

� �: 79)+ +,* �: -.���A��*���: Bvª\Z«C* Dv:E\Z«C*���: F¬¥­�n>�4*���: 0G*���: ®¯�4* °±�4*���: 2005 � 1 &²³ab+ -.��v´�*¦*�+ A���H�a�2�bµI¥�5D+ 6&2J3$]4.�f�hp�/UV* 7���2�8�9*:;,<=>� ��2?@A,2C:;,<=/"D55D+ EF�¶/KL2j 2005

1 ��������� %��·¸¹�º»'%��2 ��������� ¼��·¸¹¼��3 ��������� ](+,

529

23

� 6� 27������������: � 149.2 cm� � 41.5 kg� ��36.2�C� �� 70������ ���� 16 ���� ��114�70 mmHg� ����� ��� !�"� #$%&'��"� #(%&)*�"� +,-./01234� 56��7�� 897�"� :7;� <=>97?@� A6BCDE�"� FGHIJ�"�KLMNBCDE�"������� �Table 1�: OP� LDH 400 IU�l�ALP 525 IU�l �QR"ST� UVW KL-6 X25000 U�ml �Y�WQR� JZ[ \ P CY-FRA 43.9 ng�ml� SLX 184 U�ml� CEA 19.4 ng�ml�T4]^_`O?�������: 56 Xabc �Fig. 1�OP� de8fWghi�H%0j�kl8fWmnopWq%0jrs�tu� 56 CT �Fig. 2�OP� d S6vwW5&x�ryzi�{HJ|p}j�kl8fWmnopWs�Hq~�}jrtu�A6 CTOP� �d�Ws�p��rtu� �6 CTOP� ���W�� 6 mm�H��p��rtu� ��.�OP� F���� 5�� � 3� 5

��� d� 4����� 8��� ��6Ws�pWDE��rtu�� ��: ���W������r��"� dB6 � H¡¢£¤ £¥.¦�B6��W§¨ ¢r

Table 1. Laboratory Data

Fig. 1. Chest radiograph on admission showed irregu-

lar-shaped mass lesion in the right middle lung

field and multiple small nodular shadows in

bilateral lung fields.

Fig. 2. Chest CT scan on admission showed irregu-

lar-shaped mass lesion with pleural indentation

in the right S6 and multiple small nodular

shadows in bilateral lung fields.

©Qª« ¬­®¯ V530

24

�������� ��������� ��EBUS ����� ����������������� ����������� �!��Fig. 3A�� "�� ����� #��$�%&'()����� �** !+����,�-.� /0$1��2���������� 3 456�7�!4�� ����������5�89:0���;��<� �Fig. 3B�� �0���=>�?���@*A=>�B �� ��CD��� EE�F0��G+H��G+IFJ�����K���5���=�L5��M�N����Fig. 4�� O�� AP�!QR5 genomic DNA

�ST�� UV'W)X�YZ["� EGFR 0exon18�19�21 �\!]#?^_��[`�a�

abcde�f$����� exon21 � heterozy-gous missense mutation �L858R����� �Fig. 5��gL� ]#?^_�\!�%h0i)jkl�]#?^_mn�d0o�� !+�o�&p'1011 p�� /0$� (q>r0st T4N3M1�stage IV�N�� uv� 7B)wJ��M�Lx+y*��z{|}M~���M~0+~,-*"��%�g !+�00� .��./LR���0�g��1g2�-�34��**�A�� 5�6�!O�� 30���Z)7$��+� %�8� 79���9��<� :4:�;��R+M:�<� (q�=�LR���>���5� ?�@�(q�h*"��A�B��� j��{��0CD�,���� ��� E�F�G¡Hy*� �;��I¢�<�F�� MS �Z{Z� [£�V¤0CD�Bg �� /0$� j��{��0CD�¥J�����y*,� 15K$��� ¦� XH§¨ �Fig. 6�LR�¦� CT© �Fig. 7����ª S60�L�EE«w�� M�N���O¬:���AP!�­B:�;�O�PQ�®¯�!�� /0$� y*,� 5Y°$�� CYFRA 12.5 ng�ml,SLX 87.6 U�ml� CEA 11.7 ng�ml�!�P�R±���!�� -A���CD�²S�³´�Tµ��+ �Fig. 8��

� �

uv� ���¶��2��U" �EBUS� ����V·W�N�1�� �X¸�Y0@Z0�[� ¹@N�2�� ºZ�\g�0�����]»0^¼3�� ³

Fig. 3B. The EBUS image revealed heterogeneous

internal echoes and an irregular margin of the

lesion, with almost no vessels or bronchi within

the lesion.

Fig. 3A. The EBUS image revealed that the probe was

adjacent to the lesion because of drainage

bronchus obstruction.

Fig. 4. Histological examination of the lung tissues

obtained from TBLB biopsy with HE staining

showed adenocarcinoma cells ��100��

j��{���P�����M0 18 531

25

����������� �3����������� ������������ EBUS � �!�"#�$� 1992%� Hurter �& 26'()� 19'(*+,&-.*/01234#���4�� 5�*$78�9:*�������;���<#�$� =>?@>AB&�����C1� 25D&�

=>?@>AB*$EF�+,G�H�IJ���KLMNOLPQRSTU����<#�$VW&/X� YZ[�7� CTN\]^���K_`�/�abc^���� da���Sefgh�SiH

Fig. 5. Missense mutations in exon 21 of EGFR.

Fig. 6. Chest radiograph at 15 days after commence-

ment of gefitinib.

Note improvement of the mass lesion in right

middle lung fields and multiple small nodular

shadows in bilateral lung fields.

Fig. 7. Chest CT scan at 15 days after commencement

of gefitinib.

Note improvement of mass lesion in the right S6

and multiple small nodular shadows in bilateral

lung fields.

jklm nopq �532

26

���� EBUS ������������ ����������������� ���������������� �!"� #�$%&'�()�*$�()+�,� -��./�0!"1��2�3+45��!��� 6789���� EBUS �EBUS-GS� 4:��;�<�����6789���2������=>9?�����@�A�B�=>9?��C�!DEF()��!���4� EBUS-GS ��=>9?���4GHIJ����K�6789��L��MM� N���B���()�O���2�3+��������-�()45��!��� B�PQ� �R-� 10 mmS'��T����� 76�+U�1�����3+4���+�V����5�� T-�B�1���=>9?4�� ������WX�within� �� 87� �Y������� ���!Z�[����WX �adjacent to� �� 42� �Y��� "\#�]������^��$%_`a4&b������� 3�MM()�cd+ adjacentto +!H� eH1���fg���� hijkl���&b����$%_`a�*'Tm�()���� 3�n)�eH adjacent to �- within���3+4eH1���Yg�3+��!4H�

��!1��o��+pq-E�� :*� rc�s+,�t-�uv.�A/0+��/O12v.34'�!A4�5���Y�� 2004�� Lynch -� EGFR �w>8xhy9z�K�]D�{6O�|4/O12v.3�A��Y�}~�w�?������7����3+��V��6�� 8-�e�+� ��.)9�Y�rc�,�t-u�R 275#�}~�w�?:�v.4c�E� 25 #4;���� ;�#�d� 9#� EGFR {6O���]3!��+3�� 8#� EGFR {6O�|�<��4� A(�,;�# 7 #��EGFR{6O�|�<�-E!���+�V����� 8-�M��3� EGFR{6O�|� EGFR4 EGF�=��eH�"���TE� BE4>"����?�������3+����]H� B�����}~�w�?�e���Q2�@�TE�3+������}~�w�?4;�2��6=��|�� EGFR4�����2� EGFR ��A������+�V����� 3E-�3+eH� }~�w�?4;���"\#�]���� 3��A���]3��3+4��TE�� A(� Paez -�,�t-�u�R 119#�B�� 61�� *"� 58����Ct-���� EGFR w>8xhy9z�K�{6O���c��+3�� EGFR {6O�|�Du� ��� *"�� ,��R�E��F"<�-E� B�EGFR {6O�|��QGH O�Y�+I¡��G@GH O��Y�+�V����7�� M�Lynch -� EGFR {6O�|� 119�,�t-�u�R���� 2 �- 25 � exon �����-¢�+3�� �|4 16Y��4BE-�J� 18�-21 �Y��+�V��]H� "\#�]���w>8xhy9z���K� exon18�19�21����EGFR {6O�����+3�� exon21 � het-erozygous missense mutation �L858R� 4<�-E�� 3� L858 �8£¤¥£¤¦§�-¨lM�©�ª�KLTE���«M!¬­®¯�Y�� B���� 3��K��|4 EGFR �°��'�!�±�7q���Y�d+pq-E�� SfeH� *"�����,��R��Y�"\#�}~�w�?�v.�Q4²/³N���+O���� P��}~�w�?�Q7��+3����� ´µ� Q75¶·R���4� ¸¹�ºS�Y��»�!�K�-�()�� »�!�T1��5���� U¼!v.��!4�� "\#�ed�$%

Fig. 8. Chest CT scan at 5 months after commencement

of gefitinib.

Note improvement of mass lesion in the right S6

and multiple small nodular shadows in bilateral

lung fields.

}~�w�?4�����Du� 1# 533

27

���������� � ������������� within�������� adjacent to ����� �!"#$� %&'(�)*+,�-./+� 012!�� EBUS-GS 3 45�#$6789� EGFR :;� <�=>-7$�0?@*� AB�,CDE:F@GH-�IJ@+�

� �

1� Kurimoto N, Murayama M, Yosioka S, Nishi-saka T, Inai K and Dohi K. Assessment of the

usefulness of endobronchial tumor invasion.

Chest 1999; 5: 1500�1506.2� Barry B. Goldberg, Robert M. Steiner, Ji-BinLiu, Daniel A. Merton, Glenn Articolo,

John R. Cohn, Jonathan Gottlieb, Barbara L.

McComb and Paul W. Spirn. US-assisted bron-

choscopy with use of miniature transducer-

containing catheters. Radiology 1994; 190: 233�237.

3� Okamoto H, Watanabe K, Nagatomo A, Kuni-kane H, Aono H, Yamagata T and Kase M.

Endobronchial Ultrasonography for mediasti-

nal and hilar lymphnode metastases of lung can-

cer. Chest 2002; 121: 1498�1506.

4� Hurter TH and Hanrath P. Endobronchial

sonography. feasibility and preliminary results.

Thorax. 1992; 47: 565�567.5� KLMN� OPQN*� RSTUV�&'�WX���YZ[\]'^3�_�`� ���a 2005; 27: 290�295.

6� Thomas J. Lynch, Daphne W. Bell, Ra#aellaSordella, Sarada Gurubhagavatula, Ross A.

Okimoto, Brian W. Brannigan, Patricia L. Har-

ris, Sara M. Haserlat, Je#reyG. Supko, Frank

G. Haluska, David N. Louis, David C. Christi-

ani, Je# Settleman and Daniel A. Haber. Acti-

vating mutations in the epidermal growth factor

receptor underlying responsiveness of non-

small-cell lung cancer to gefitinib. N Engl J Med

2004; 350: 2129�2139.7� J. Guillermo Paez, Pasi A. Janne, Je#rey C. Lee,Sean Tracy, Heidi Greulich, Stacey Gabriel,

Paula Herman, Frederic J. Kaye, Neal Linde-

man, Titus J. Boggon, Katsuhiko Naoki, Hide-

fumi Sasaki, Yoshitaka Fujii, Michael J. Eck,

William R. Sellers, Bruce E. Johnson and Mat-

thewMeyerson. EGFRmutation in lung cancer:

correlation with clinical response to gefitinib

therapy. Science 2004; 304: 1497�1500�

bcde KLMN *534

28

Abstract

A Case of Pulmonary adenocarcinoma with EGFR Mutation Diagnosed

by Endobronchial Ultrasonography with Guide Sheath

�EBUS-GS� Successfully Treated with Gefitinib.

Takeo Inoue1, Noriaki Kurimoto2, Miho Nakamura1, Masahiro Ohsige1,

Atsuko Ishida1, Junko Sagi1, Yoshitugu Fujita1, Yuka Matsuoka1,

Taeko Shirakawa1, Mamoru Tadokoro3, Teruomi Miyazawa1,

and Hiroaki Osada.2

A 79-year-old Japanese woman with no smoking habit was referred to our hospital complaining of

anterior chest pain. Chest CT showed a mass in the right middle lobe and multiple pulmonary nodules in

both lungs. For further examination, we performed transbronchial lung biopsy using endobronchial

ultrasonography with a guide sheath �EBUS-GS�� Biopsy specimens of the lung revealed adenocarcinoma,and she was diagnosed as lung cancer with multiple pulmonary metastases. We searched for the EGFR gene

mutations in one of the primary tumor specimens, and an exon 21 missense mutation �L858R� was detected.Subsequently, we initiated gefitinib, and it acted dramatically on both primary tumor and pulmonary

metastases. Since EGFR gene analysis needed a fair amount of tumor cells, it has been mainly analyzed by

surgically resected specimens. However, as EBUS-GS makes it possible to obtain biopsy specimens at better

site, it is expected that EGFR gene analysis will be performed with less invasive method using EBUS-GS.

1 Division of Respiratory and Infectious Disease, Department of Internal Medicine, St. Marianna University School

of Medicine

2 Department of Chest Surgery, St. Marianna University School of Medicine

3 Department of Diagnostic Pathology, St. Marianna University School of Medicine

���������� �� 1� 535

29

Recommended