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Clinical Investigations: CANCER |

Immunohistochemical KIT (CD117) Expression in Thymic Epithelial Tumors* FREE TO VIEW

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

*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@ncc.go.jp



Chest. 2005;128(1):140-144. doi:10.1378/chest.128.1.140
Text Size: A A A
Published online

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.

Figures in this Article

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.1However, 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,24 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 reported57 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).8Its 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.915 Molecular targeted therapy against KIT has become a standard treatment of choice in patients with AML and GIST.16The 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.

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.

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.

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).

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.

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.8Mainly from immunohistochemical studies9,1112 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.915 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.16,2027 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.,24 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.24 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.57 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.

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.

Table Graphic Jump Location
Table 1. Expression of KIT in Thymoma*
* 

− = negative staining; 1 + = staining (< 10% of tumor cells); 2 + = staining (10 to 50%); 3 + = staining (> 50% of tumor cells).

 

This thymoma is composed of spindle cells with mild atypia and is probably classified as an atypical thymoma, although it belongs to the type A histologic subtype in the World Health Organization classification.

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

See Table 1 for terms not used in the text.

Figure Jump LinkFigure 1. Thymic carcinoma (epidermoid nonkeratinizing carcinoma), showing diffuse membranous staining for KIT. Top: hematoxylin-eosin, original ×100. Bottom: immunoperoxidase stain, original ×100.Grahic Jump Location
Table Graphic Jump Location
Table 3. Simultaneous Expression of KIT and CD5*
* 

n = 20.

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.

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:
 
Suster, S, Rosai, J Thymic carcinoma: a clinicopathologic study of 60 cases.Cancer1991;15(67),1025-1032
 
Hsu, CP, Chen, CY, Chen, CL, et al Thymic carcinoma: ten years’ experience in twenty patients.J Thorac Cardiovasc Surg1994;107,615-620. [PubMed]
 
Lucchi, M, Mussi, A, Basolo, F, et al The multimodality treatment of thymic carcinoma.Eur J Cardiothorac Surg2001;19,566-569. [CrossRef] [PubMed]
 
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 Pathol1996;106,483-486. [PubMed]
 
Hishima, T, Fukayama, M, Fujisawa, M, et al CD5 expression in thymic carcinoma.Am J Pathol1994;145,268-275. [PubMed]
 
Dorfman, DM, Shahsafaei, A, Chan, JK Thymic carcinomas, but not thymomas and carcinomas of other sites, show CD5 immunoreactivity.Am J Surg Pathol1997;21,936-940. [CrossRef] [PubMed]
 
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 J1987;6,3341-3351. [PubMed]
 
Natali, PG, Nicotra, MR, Sures, I, et al Expression of c-kit receptor in normal and transformed human nonlymphoid tissues.Cancer Res1992;52,6139-6143. [PubMed]
 
Turner, AM, Zsebo, KM, Martin, F, et al Nonhematopoietic tumor cell lines express stem cell factor and display c-kit receptors.Blood1992;80,374-381. [PubMed]
 
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 Arch1994;424,135-141. [PubMed]
 
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 Pathol1993;142,339-346. [PubMed]
 
Sarlomo-Rikala, M, Kovatich, AJ, Barusevicius, A, et al CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34.Mod Pathol1998;11,728-734. [PubMed]
 
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.Leukemia1996;10,288-296. [PubMed]
 
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 Pathol1998;29,498-504. [CrossRef] [PubMed]
 
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 Oncol2002;20,1692-1703. [CrossRef] [PubMed]
 
Henley, JD, Cummings, OW, Loehrer, PJ, Sr Tyrosine kinase receptor expression in thymomas.J Cancer Res Clin Oncol2004;130,222-224. [CrossRef] [PubMed]
 
Pan, CC, Chen, PC, Chiang, H KIT (CD117) is frequently overexpressed in thymic carcinomas but is absent in thymomas.J Pathol2004;202,375-381. [CrossRef] [PubMed]
 
Rosai, J Histological typing of tumors of the thymus: World Health Organization, international histological classification of tumors 2nd ed.1999 Springer-Verlag. New York:
 
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 Res2001;61,6281-6289. [PubMed]
 
Kondoh, G, Hayasaka, N, Li, Q, et al Anin vivomodel for receptor tyrosine kinase autocrine/paracrine activation: auto-stimulated KIT receptor acts as a tumor promoting factor in papillomavirus-induced tumorigenesis.Oncogene1995;10,341-347. [PubMed]
 
Sekido, Y, Obata, Y, Ueda, R, et al Preferential expression of c-kit protooncogene transcripts in small cell lung cancer.Cancer Res1991;51,2416-2419. [PubMed]
 
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 Res1993;53,1709-1714. [PubMed]
 
Cohen, PS, Chan, JP, Lipkunskaya, M, et al Expression of stem cell factor and c-kit in human neuroblastoma: the Children’s Cancer Group.Blood1994;84,3465-3472. [PubMed]
 
Hirota, S, Isozaki, K, Moriyama, Y, et al Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.Science1998;279,577-580. [CrossRef] [PubMed]
 
Tian, Q, Frierson, HF, Jr, Krystal, GW, et al Activating c-kit gene mutations in human germ cell tumors.Am J Pathol1999;154,1643-1647. [CrossRef] [PubMed]
 
Piao, X, Bernstein, A A point mutation in the catalytic domain of c-kit induces growth factor independence, tumorigenicity, and differentiation of mast cells.Blood1996;87,3117-3123. [PubMed]
 
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 Med2004;128,538-543. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Thymic carcinoma (epidermoid nonkeratinizing carcinoma), showing diffuse membranous staining for KIT. Top: hematoxylin-eosin, original ×100. Bottom: immunoperoxidase stain, original ×100.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Expression of KIT in Thymoma*
* 

− = negative staining; 1 + = staining (< 10% of tumor cells); 2 + = staining (10 to 50%); 3 + = staining (> 50% of tumor cells).

 

This thymoma is composed of spindle cells with mild atypia and is probably classified as an atypical thymoma, although it belongs to the type A histologic subtype in the World Health Organization classification.

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

See Table 1 for terms not used in the text.

Table Graphic Jump Location
Table 3. Simultaneous Expression of KIT and CD5*
* 

n = 20.

References

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:
 
Suster, S, Rosai, J Thymic carcinoma: a clinicopathologic study of 60 cases.Cancer1991;15(67),1025-1032
 
Hsu, CP, Chen, CY, Chen, CL, et al Thymic carcinoma: ten years’ experience in twenty patients.J Thorac Cardiovasc Surg1994;107,615-620. [PubMed]
 
Lucchi, M, Mussi, A, Basolo, F, et al The multimodality treatment of thymic carcinoma.Eur J Cardiothorac Surg2001;19,566-569. [CrossRef] [PubMed]
 
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 Pathol1996;106,483-486. [PubMed]
 
Hishima, T, Fukayama, M, Fujisawa, M, et al CD5 expression in thymic carcinoma.Am J Pathol1994;145,268-275. [PubMed]
 
Dorfman, DM, Shahsafaei, A, Chan, JK Thymic carcinomas, but not thymomas and carcinomas of other sites, show CD5 immunoreactivity.Am J Surg Pathol1997;21,936-940. [CrossRef] [PubMed]
 
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 J1987;6,3341-3351. [PubMed]
 
Natali, PG, Nicotra, MR, Sures, I, et al Expression of c-kit receptor in normal and transformed human nonlymphoid tissues.Cancer Res1992;52,6139-6143. [PubMed]
 
Turner, AM, Zsebo, KM, Martin, F, et al Nonhematopoietic tumor cell lines express stem cell factor and display c-kit receptors.Blood1992;80,374-381. [PubMed]
 
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 Arch1994;424,135-141. [PubMed]
 
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 Pathol1993;142,339-346. [PubMed]
 
Sarlomo-Rikala, M, Kovatich, AJ, Barusevicius, A, et al CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34.Mod Pathol1998;11,728-734. [PubMed]
 
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.Leukemia1996;10,288-296. [PubMed]
 
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 Pathol1998;29,498-504. [CrossRef] [PubMed]
 
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 Oncol2002;20,1692-1703. [CrossRef] [PubMed]
 
Henley, JD, Cummings, OW, Loehrer, PJ, Sr Tyrosine kinase receptor expression in thymomas.J Cancer Res Clin Oncol2004;130,222-224. [CrossRef] [PubMed]
 
Pan, CC, Chen, PC, Chiang, H KIT (CD117) is frequently overexpressed in thymic carcinomas but is absent in thymomas.J Pathol2004;202,375-381. [CrossRef] [PubMed]
 
Rosai, J Histological typing of tumors of the thymus: World Health Organization, international histological classification of tumors 2nd ed.1999 Springer-Verlag. New York:
 
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 Res2001;61,6281-6289. [PubMed]
 
Kondoh, G, Hayasaka, N, Li, Q, et al Anin vivomodel for receptor tyrosine kinase autocrine/paracrine activation: auto-stimulated KIT receptor acts as a tumor promoting factor in papillomavirus-induced tumorigenesis.Oncogene1995;10,341-347. [PubMed]
 
Sekido, Y, Obata, Y, Ueda, R, et al Preferential expression of c-kit protooncogene transcripts in small cell lung cancer.Cancer Res1991;51,2416-2419. [PubMed]
 
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 Res1993;53,1709-1714. [PubMed]
 
Cohen, PS, Chan, JP, Lipkunskaya, M, et al Expression of stem cell factor and c-kit in human neuroblastoma: the Children’s Cancer Group.Blood1994;84,3465-3472. [PubMed]
 
Hirota, S, Isozaki, K, Moriyama, Y, et al Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.Science1998;279,577-580. [CrossRef] [PubMed]
 
Tian, Q, Frierson, HF, Jr, Krystal, GW, et al Activating c-kit gene mutations in human germ cell tumors.Am J Pathol1999;154,1643-1647. [CrossRef] [PubMed]
 
Piao, X, Bernstein, A A point mutation in the catalytic domain of c-kit induces growth factor independence, tumorigenicity, and differentiation of mast cells.Blood1996;87,3117-3123. [PubMed]
 
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 Med2004;128,538-543. [PubMed]
 
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