Chest ACCP Member Benefits
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nakagawa, K.
Right arrow Articles by Tsuchiya, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nakagawa, K.
Right arrow Articles by Tsuchiya, R.
Related Content
Right arrowRelated Article
(Chest. 2005;128:140-144.)
© 2005 American College of Chest Physicians

Immunohistochemical KIT (CD117) Expression in Thymic Epithelial Tumors*

Kazuo Nakagawa, MD; Yoshihiro Matsuno, MD; Hideo Kunitoh, MD; Arafumi Maeshima, MD; Hisao Asamura, MD and Ryosuke Tsuchiya, MD

* From the Departments of Pathology (Drs. Nakagawa, Matsuno, and Maeshima), Medical Oncology (Dr. Kunitoh), and Thoracic Surgery (Drs. Asamura and Tsuchiya), National Cancer Center Hospital and Research Institute, Tokyo, Japan.

Correspondence to: Yoshihiro Matsuno, MD, Department of Pathology, National Cancer Center Hospital, 1–1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan; e-mail: ymatsuno{at}ncc.go.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: It is sometimes very difficult both clinically and pathologically to distinguish thymic epithelial tumors from primary lung carcinoma with massive anterior mediastinal involvement. The expression of KIT (CD117) in thymic epithelial tumors was investigated in order to evaluate its usefulness as a marker supporting differential diagnosis and choice of therapy.

Methods: We examined the immunohistochemical expression of KIT in 70 resected thymic epithelial tumors (thymomas, 50; thymic carcinomas, 20) that had been reclassified on the basis of the World Health Organization histologic classification system. We also compared the expression of KIT and CD5 in 20 thymic carcinomas with their expression in 20 resected pulmonary squamous cell carcinomas that were spreading directly into the mediastinum.

Results: Of the 50 thymomas, only 2 (4%) showed positive immunoreactivity for KIT (type A thymoma, 1; type B3 thymoma, 1), whereas 16 of the 20 thymic carcinomas (80%) showed positive immunoreactivity. Testing was positive for CD5 in 14 of the 20 thymic carcinomas (70%). In the pulmonary squamous cell carcinomas, in contrast, the immunohistochemical expression of KIT and CD5 was found in only 4 of 20 carcinomas (20%) and 3 of 20 carcinomas (15%), respectively. Furthermore, of the 40 specimens examined (either thymic or lung carcinoma) all 13 that were positive for both KIT and CD5 were thymic carcinomas, and 13 of the 16 that were negative for both were lung carcinomas.

Conclusion: KIT expression is a useful immunohistochemical marker for the diagnosis of thymic carcinoma, and its examination in combination with CD5 immunohistochemistry would greatly help in the differential diagnosis of primary thymic carcinoma from pulmonary squamous cell carcinoma. Further investigations at a genetic level should be encouraged, not only to define the role of KIT in the oncogenesis of thymic epithelial tumors, but also to establish target-based therapy.

Key Words: c-kit • KIT • thymic carcinoma • thymic epithelial tumor • thymoma


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
It is often difficult, not only by radiographic imaging but also by pathologic examination, to distinguish thymic epithelial tumors (ie, thymomas or thymic carcinomas) from primary lung carcinomas of the central type involving the mediastinum.1 However, these three tumors must be distinguished from each other because the treatment of choice is obviously different for each of them. A chance of cure may be lost by a misdiagnosis of thymoma or localized primary thymic carcinoma as advanced lung carcinoma with massive mediastinal involvement. Moreover, the thymic carcinoma shows a better response to chemotherapy or radiotherapy, and hence better patient outcome,234 whereas the latter shows more frequent regional lymph node involvement and distant metastasis.

In daily practice, differential diagnosis between those two different tumors depends on several parameters that are not necessarily specific, that is, smoking history (favors lung cancer), the main location of the tumor (pulmonary hilum vs anterior mediastinum), and the presence of abundant hyalinized collagenous stroma or abrupt keratinization simulating Hassall corpuscles (favors thymic carcinoma). Although immunoreactive CD5 has been reported567 as a useful marker for primary thymic squamous cell carcinoma in routine surgical pathology, it is still necessary to identify other diagnostic markers to make this differential diagnosis more reliable.

We investigated the immunohistochemical expression of KIT (CD117) in primary thymic carcinoma. KIT, a protein product of the c-kit protooncogene, is a transmembrane tyrosine kinase receptor and is a growth factor receptor for stem cell factor (SCF).8 Its expression has been documented in a wide variety of human neoplasms, including acute myeloid leukemia (AML), mast cell tumor, germ cell tumor, ovarian carcinoma, malignant melanoma, GI stromal tumor (GIST), small cell lung carcinoma (SCLC), neuroblastoma, and breast carcinoma.9101112131415 Molecular targeted therapy against KIT has become a standard treatment of choice in patients with AML and GIST.16 The expression of KIT in thymic epithelial tumors has been reported very recently.1718 We examined KIT expression in these tumors immunohistochemically and evaluated the usefulness of immunoreactive KIT as a diagnostic marker in primary thymic carcinoma.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tumors
There were 161 resected thymic epithelial tumors in the pathology file of the National Cancer Center Hospital, Tokyo, Japan. We reviewed hematoxylin-eosin-stained sections of each specimen to determine its histologic subtype on the basis of the World Health Organization histologic classification.19 Accordingly, 50 cases of thymomas (5 histologic subtypes, 10 each) and 20 cases of thymic carcinomas (epidermoid carcinomas, 5; nonkeratinizing epidermoid carcinomas, 11; basaloid carcinoma, 1; papillary carcinoma, 1; undifferentiated carcinoma, 1) were extracted from the files and employed in this study. Four patients with thymoma (two patients with type B2 and two patients with type B3 received preoperative chemotherapy, and three patients with thymic carcinoma received preoperative therapy; two patients underwent chemotherapy, and one patient underwent chemoradiotherapy.

In addition, 20 resected specimens of primary squamous cell carcinoma of the lung (10 well-differentiated to moderately differentiated carcinomas and 10 poorly differentiated carcinomas) involving the anterior mediastinum were also extracted and analyzed immunohistochemically for comparison. Primary lung carcinomas showing massive involvement in the anterior mediastinum were excluded from the study to avoid confusion with thymic carcinoma.

Immunohistochemistry
Immunohistochemistry was performed on representative formalin-fixed paraffin sections. The sections were autoclaved for 10 min in 10 mmol/L citrate buffer (pH, 6.0) for antigen retrieval before incubation with a primary antibody. Two monoclonal antibodies, anti-KIT (Dako; Glostrup, Denmark) and anti-CD5 (NCL-CD5–4C5; Novocastra; Newcastle-on-Tyne, UK) were used as primary antibodies. Immunoreaction was detected by a labeled streptavidin-biotin method and was visualized with 3,3'-diaminobendizine, followed by counterstaining with hematoxylin. The degree of immunostaining of those two markers was scored as follows: –, negative staining; 1+, staining (ie, < 10% of tumor cells stained); 2+, staining (ie, 10 to 50% stained); and 3+, staining (ie, > 50% stained). KIT staining was judged to be positive when unequivocal membranous staining was observed along the cell membrane.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
KIT Immunoreactivity in Thymomas
First, we studied the immunohistochemical KIT expression in thymomas (Table 1 ). Of the 50 thymomas examined, only 2 (4%) were positive for KIT, one of which was a type A thymoma and the other one was a type B3. Although the former specimen was classified as a type A thymoma, this tumor was composed of spindle cells with mild atypia. The other thymomas were completely negative for KIT staining in both the epithelial cells and lymphocytes.


View this table:
[in this window]
[in a new window]

  		Table 1.. Expression of KIT in Thymoma*

 
KIT Immunoreactivity in Thymic Carcinomas and Pulmonary Squamous Cell Carcinomas
Next, we examined and compared the expression of immunoreactive KIT in thymic carcinomas and pulmonary squamous cell carcinomas. The results are presented in Table 2 . Of the 20 thymic carcinomas, 16 (80%) were positive for KIT (keratinizing epidermoid [squamous cell] carcinomas, 3 of 5; nonkeratinizing epidermoid carcinomas, 10 of 11; basaloid carcinoma, 1; undifferentiated carcinomas, 2). The papillary carcinoma was negative for KIT. Thymic carcinomas that were positive for KIT exhibited predominantly membrane staining (Fig 1 ). In contrast, only 4 of 20 pulmonary squamous cell carcinomas (20%) were positive for KIT (well-differentiated or moderately differentiated carcinomas, 2; poorly differentiated carcinomas, 2).


View this table:
[in this window]
[in a new window]

  		Table 2.. Expression of KIT and CD5 in Thymic Carcinoma and Pulmonary Squamous Cell Carcinoma*

 


View larger version (154K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1.. Thymic carcinoma (epidermoid nonkeratinizing carcinoma), showing diffuse membranous staining for KIT. Top: hematoxylin-eosin, original x100. Bottom: immunoperoxidase stain, original x100.

 
Comparison of CD5 Immunoreactivity in Thymic Carcinoma and Pulmonary Squamous Cell Carcinoma
Because it is widely known that CD5 is a supportive immunohistochemical marker for thymic carcinoma, we examined CD5 expression in thymic carcinoma and pulmonary squamous cell carcinoma to compare it with the results obtained for KIT. Of the 20 thymic carcinomas, 14 (70%) were positive for CD5 (keratinizing epidermoid carcinomas, 2 of 5; nonkeratinizing epidermoid carcinomas, 9 of 11; the basaloid carcinoma, 1; the undifferentiated carcinoma, 1; the papillary carcinoma, 1). In contrast, only 3 of 20 pulmonary squamous cell carcinomas (15%) were positive for CD5 (well-differentiated or moderately differentiated carcinomas, 1; poorly differentiated carcinomas, 2). The immunoreactivity for KIT in thymic carcinomas and pulmonary squamous cell carcinomas was almost equal to that for CD5. Furthermore, of the 40 specimens (either thymic or lung carcinoma) examined immunohistochemically, 13 displayed positivity for both KIT and CD5 (Table 3 ). All of them (100%) were thymic carcinomas. None of the pulmonary squamous cell carcinomas was positive for both markers. Of the 11 specimens that were positive for only one of the two markers, 4 specimens were thymic carcinomas and 7 were pulmonary carcinomas. Sixteen of the 40 specimens were negative for both markers. They consisted of 3 thymic carcinomas and 13 pulmonary squamous cell carcinomas.


View this table:
[in this window]
[in a new window]

  		Table 3.. Simultaneous Expression of KIT and CD5*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
KIT is the protein product of the c-kit protooncogene and is immunologically identified by the CD117 antigenic epitope. Functionally, it is a transmembrane tyrosine kinase receptor the physiologic ligand of which is cytokine SCF, also called mast cell growth factor or Steel factor.8 Mainly from immunohistochemical studies91112 in human tissue, it has been postulated that KIT plays an important role in multiple cellular functions, including survival, proliferation, adhesion, differentiation, and functional maturation. KIT expression has also been reported in a wide variety of human solid tumors, such as mast cell tumors, germ cell tumors, ovarian carcinomas, malignant melanomas, GISTs, SCLCs, neuroblastomas, and breast carcinomas, and is thought to be largely implicated in the development of these tumors.9101112131415 However, only a few studies1718 have been done to evaluate its expression in thymic epithelial tumors. We examined the immunohistochemical expression of KIT in resected thymic epithelial tumors, and demonstrated that most thymic carcinomas (80%) were positive for KIT and that most thymomas (96%) were negative for KIT. In accordance with these results, thymic carcinoma should be added to the list of KIT-positive tumors.

The following three general mechanisms of KIT activation in tumor cells have been recognized: (1) autocrine and/or paracrine stimulation of the receptor by its ligand; (2) cross-activation by other kinases and/or loss of regulatory phosphatase activity; and (3) acquisition of activating mutation.162021222324252627 In SCLC, because the coexpression of SCF and KIT has been demonstrated, autocrine mechanisms may play a role in tumor initiation and progression.2223 In contrast, the activation of a mutation in the c-kit gene is thought to be the most important factor in the pathogenesis of GISTs.25 Moreover, elevated kinase activity caused by a c-kit gene mutation is now utilized as a molecular target of therapy for GISTs. In thymic epithelial tumors, as shown by our data, frequent and strong KIT expression appears to be closely associated with malignancy, because thymic carcinoma is more aggressive than thymoma and is highly lethal.234 Thus, KIT must play an important role in the acquisition of a malignant phenotype in thymic epithelial tumors. Its molecular mechanism is still to be clarified.

The above discussion is obviously relevant to therapeutic strategies for thymic carcinoma. To date, no standard medical therapy has been established in the field of thymic epithelial tumors, particularly for thymic carcinoma.234 If the activation of a mutation in the catalytic domain of the c-kit gene is the causative event in thymic carcinoma, as is the case in AML and GISTs, molecular target therapy using a specific kinase inhibitor would be indicated. Although most studies of KIT-positive human solid tumors have failed so far to identify the activating c-kit gene mutation, this avenue should still be investigated in thymic carcinomas in an effort to make an effective therapy available.

Shimosato and Mukai1 noted that in poorly differentiated squamous cell carcinomas, mucoepidermoid carcinomas, small cell neuroendocrine carcinomas, clear cell carcinomas, and sarcomatoid carcinomas, the distinction between thymic carcinoma and lung carcinoma was difficult, and depended largely or entirely on the location of the primary tumor and lymph node metastasis. Differential diagnosis would be even more challenging if needle biopsy specimens were submitted. As an ancillary examination, immunoreactive CD5 is the only marker available in routine surgical pathology that supports the diagnosis of thymic carcinoma against lung carcinoma.567 In our study, KIT was positive in a significant proportion of thymic carcinomas (16 of 20; 80%), whereas it was negative in most pulmonary squamous cell carcinomas (16 of 20; 80%) as one recent study shows.28 Thus, it is reasonable to conclude that KIT is another useful immunohistochemical marker for thymic carcinoma. In combination with CD5, it should provide a more powerful tool for distinguishing between thymic carcinoma and lung carcinoma, because our data indicate that tumors that are positive for both KIT and CD5 are almost exclusively thymic carcinomas. In contrast, when a tumor is negative for both KIT and CD5, it is probably a lung carcinoma involving the mediastinum.

Precise differential diagnosis by the examination of pathologic specimens, aided by this effective examination and an elucidation of the molecular mechanisms of KIT activation, will most probably promote the establishment of a standard therapy for thymic carcinoma in the near future.


   Acknowledgements
 
The authors are grateful to Ms. T. Shimizu, Clinical Laboratory Division, for technical assistance and to Ms. M. Suzuki, Pathology Division, for secretarial work. They also thank Mr. S. Tamura, Photocenter, for his photographic work.


   Footnotes
 
Abbreviations: AML = acute myeloid leukemia; GIST = GI stromal tumor; SCF = stem cell factor; SCLC = small cell lung carcinoma

This work was supported in part by Grants-in-Aid for Cancer Research (12–5, 14S-4, and 16–6) from the Ministry of Health, Labor, and Welfare of Japan.

Received for publication May 19, 2004. Accepted for publication November 9, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Shimosato, Y, Mukai, K (1997) Tumors of the mediastinum. Rosai, J Sobin, LH eds. Atlas of tumor pathology. 3rd series, fascicle 21 ,40-120 The Armed Forces Institute of Pathology. Washington, DC:
  2. Suster, S, Rosai, J Thymic carcinoma: a clinicopathologic study of 60 cases. Cancer 1991;15(67),1025-1032
  3. Hsu, CP, Chen, CY, Chen, CL, et al Thymic carcinoma: ten years’ experience in twenty patients. J Thorac Cardiovasc Surg 1994;107,615-620[Abstract/Free Full Text]
  4. Lucchi, M, Mussi, A, Basolo, F, et al The multimodality treatment of thymic carcinoma. Eur J Cardiothorac Surg 2001;19,566-569[Abstract/Free Full Text]
  5. Berezowski, K, Grimes, MM, Gal, A, et al CD5 immunoreactivity of epithelial cells in thymic carcinoma and CASTLE using paraffin-embedded tissue. Am J Clin Pathol 1996;106,483-486[ISI][Medline]
  6. Hishima, T, Fukayama, M, Fujisawa, M, et al CD5 expression in thymic carcinoma. Am J Pathol 1994;145,268-275[Abstract]
  7. Dorfman, DM, Shahsafaei, A, Chan, JK Thymic carcinomas, but not thymomas and carcinomas of other sites, show CD5 immunoreactivity. Am J Surg Pathol 1997;21,936-940[CrossRef][ISI][Medline]
  8. Yarden, Y, Kuang, WJ, Yang-Feng, T, et al Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 1987;6,3341-3351[ISI][Medline]
  9. Natali, PG, Nicotra, MR, Sures, I, et al Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res 1992;52,6139-6143[Abstract/Free Full Text]
  10. Turner, AM, Zsebo, KM, Martin, F, et al Nonhematopoietic tumor cell lines express stem cell factor and display c-kit receptors. Blood 1992;80,374-381[Abstract/Free Full Text]
  11. Tsuura, Y, Hiraki, H, Watanabe, K, et al Preferential localization of c-kit product in tissue mast cells, basal cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in human: immunohistochemical study on formalin-fixed, paraffin-embedded tissues. Virchows Arch 1994;424,135-141[ISI][Medline]
  12. Matsuda, R, Takahashi, T, Nakamura, S, et al Expression of the c-kit protein in human solid tumors and in corresponding fetal and adult normal tissues. Am J Pathol 1993;142,339-346[Abstract]
  13. Sarlomo-Rikala, M, Kovatich, AJ, Barusevicius, A, et al CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol 1998;11,728-734[ISI][Medline]
  14. Cole, SR, Aylett, GW, Harvey, NL, et al Increased expression of c-Kit or its ligand Steel Factor is not a common feature of adult acute myeloid leukaemia. Leukemia 1996;10,288-296[ISI][Medline]
  15. Arber, DA, Tamayo, R, Weiss, LM Paraffin section detection of the c-kit gene product (CD117) in human tissues: value in the diagnosis of mast cell disorders. Hum Pathol 1998;29,498-504[CrossRef][ISI][Medline]
  16. Heinrich, MC, Blanke, CD, Druker, BJ, et al Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 2002;20,1692-1703[Abstract/Free Full Text]
  17. Henley, JD, Cummings, OW, Loehrer, PJ, Sr Tyrosine kinase receptor expression in thymomas. J Cancer Res Clin Oncol 2004;130,222-224[CrossRef][ISI][Medline]
  18. Pan, CC, Chen, PC, Chiang, H KIT (CD117) is frequently overexpressed in thymic carcinomas but is absent in thymomas. J Pathol 2004;202,375-381[CrossRef][ISI][Medline]
  19. Rosai, J Histological typing of tumors of the thymus: World Health Organization, international histological classification of tumors 2nd ed. 1999 Springer-Verlag. New York:
  20. Caceres-Cortes, JR, Alvarado-Moreno, JA, Waga, K, et al Implication of tyrosine kinase receptor and steel factor in cell density-dependent growth in cervical cancers and leukemias. Cancer Res 2001;61,6281-6289[Abstract/Free Full Text]
  21. Kondoh, G, Hayasaka, N, Li, Q, et al An in vivo model for receptor tyrosine kinase autocrine/paracrine activation: auto-stimulated KIT receptor acts as a tumor promoting factor in papillomavirus-induced tumorigenesis. Oncogene 1995;10,341-347[ISI][Medline]
  22. Sekido, Y, Obata, Y, Ueda, R, et al Preferential expression of c-kit protooncogene transcripts in small cell lung cancer. Cancer Res 1991;51,2416-2419[Abstract/Free Full Text]
  23. Sekido, Y, Takahashi, T, Ueda, R, et al Recombinant human stem cell factor mediates chemotaxis of small-cell lung cancer cell lines aberrantly expressing the c-kit protooncogene. Cancer Res 1993;53,1709-1714[Abstract/Free Full Text]
  24. Cohen, PS, Chan, JP, Lipkunskaya, M, et al Expression of stem cell factor and c-kit in human neuroblastoma: the Children’s Cancer Group. Blood 1994;84,3465-3472[Abstract/Free Full Text]
  25. Hirota, S, Isozaki, K, Moriyama, Y, et al Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279,577-580[Abstract/Free Full Text]
  26. Tian, Q, Frierson, HF, Jr, Krystal, GW, et al Activating c-kit gene mutations in human germ cell tumors. Am J Pathol 1999;154,1643-1647[Abstract/Free Full Text]
  27. Piao, X, Bernstein, A A point mutation in the catalytic domain of c-kit induces growth factor independence, tumorigenicity, and differentiation of mast cells. Blood 1996;87,3117-3123[Abstract/Free Full Text]
  28. Butnor, KJ, Burchette, JL, Sporn, TA, et al The spectrum of Kit (CD117) immunoreactivity in lung and pleural tumors: a study of 96 cases using a single-source antibody with a review of the literature. Arch Pathol Lab Med 2004;128,538-543[ISI][Medline]

Related Article

Correction for Volume 129, p. 140
Chest 2006 129: 831. [Full Text] [PDF]



This article has been cited by other articles:


Home page
 J. Immunol.Home page
X. Zhu, H. J. Belmont, S. Price-Schiavi, B. Liu, H.-i. Lee, M. Fernandez, R. L. Wong, J. Builes, P. R. Rhode, and H. C. Wong
Visualization of p53264-272/HLA-A*0201 Complexes Naturally Presented on Tumor Cell Surface by a Multimeric Soluble Single-Chain T Cell Receptor.
J. Immunol., March 1, 2006; 176(5): 3223 - 3232.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nakagawa, K.
Right arrow Articles by Tsuchiya, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nakagawa, K.
Right arrow Articles by Tsuchiya, R.
Related Content
Right arrowRelated Article

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS