Elsevier

Lung Cancer

Volume 62, Issue 3, December 2008, Pages 321-325
Lung Cancer

Absence of gene mutations in KIT-positive thymic epithelial tumors

https://doi.org/10.1016/j.lungcan.2008.03.035Get rights and content

Summary

Background

Overexpression of KIT, a tyrosine kinase receptor protein encoded by the proto-oncogene c-kit, is observed in human neoplasms such as gastrointestinal stromal tumors (GISTs), myeloproliferative disorders, melanoma and seminoma. In patients with GIST, overexpression of mutated KIT within the tumor is predictive of response to molecular targeted therapy using imatinib. However, the role of KIT expression in thymic carcinoma is not fully understood.

Methods

Thymic epithelial tumors from 37 patients (17 thymic carcinomas and 20 thymomas) were examined. Immunohistochemical staining with anti-KIT polyclonal antibody and anti-CD5 was performed. Mutation analyses in the juxtamembrane domains, exons 9 and 11, and in the tyrosine kinase domains, exons 13 and 17, were undertaken using polymerase chain reaction (PCR) and direct DNA sequencing in KIT-positive samples.

Results

KIT- and CD5-positive staining was observed only in thymic carcinoma. Percentage of positive staining was 100% in squamous cell carcinoma, with no positive staining in other histologies, including atypical carcinoid. Mutation analysis of the KIT gene was performed in 11 squamous cell carcinomas, 1 adenocarcinoma and 1 adenosquamous cell carcinoma. None of the tested samples showed mutations in any of the four exons.

Conclusions

Squamous cell carcinoma of the thymus frequently expressed KIT and CD5 proteins, whereas other tumors did not. Unlike GIST, overexpression of KIT does not necessarily indicate gene mutation in thymic carcinoma. KIT and CD5 appear useful for evaluating and subtyping thymic epithelial tumors.

Introduction

Thymic carcinoma is a highly malignant tumor of the mediastinum that preferentially arises in elderly adults. The 5-year survival rate is only 30–50% [1] and aggressive multimodal therapeutic approaches are required. To establish optimal treatment strategies for patients with malignant tumor of the mediastinum, both radiographic evaluation and histological diagnosis are crucial. However, establishing a definitive diagnosis from the little amount of specimen taken by biopsy is sometimes difficult. Novel markers that enable accurate diagnosis using a small sample are thus required. KIT (CD117) is a tyrosine kinase receptor protein encoded by the proto-oncogene c-kit [2], [3], and activating mutations in KIT have been reported in many malignancies. KIT is frequently expressed in normal tissues, including hematopoietic stem cells, mast cells, melamocytes and germ cells [4]. Overexpression of KIT is also observed in several human neoplasms, such as gastrointestinal stromal tumors (GISTs) [5], myeloproliferative disorders [6], melanoma [7] and seminoma [8]. Regarding frequencies of immunohistochemical KIT expression in thymic epithelial tumors, several reports have demonstrated diagnostic value of KIT expression [9], [10], [11]. However, gene mutations have not been systematically clarified in thymic tumors. In patients with GIST, overexpression of mutated KIT within tumor can predict response to molecular targeted therapy using imatinib mesylate, an adenosine triphosphate-competitive inhibitor of Abl tyrosine kinases [12]. KIT expression and the presence of mutated KIT may thus provide important information regarding molecular targeted treatments. Strobel et al. reported the first case of thymic carcinoma that showed overexpression of mutated KIT, in a patient who responded to imatinib [13]. Based on that report, we hypothesized that KIT expression and mutation might be useful for diagnosis and treatment of thymic carcinoma. In this study, KIT expression was determined by immunohistochemical staining and mutation of KIT was also examined using paraffin-embedded specimens.

Section snippets

Materials and methods

Thymic epithelial tumors from 37 patients who underwent surgical resection at Niigata University Hospital were examined. Specimens were classified according to World Health Organization (WHO) classifications [14] and were staged according to the criteria outlined by Masaoka et al. [15]. In all cases, hematoxylin and eosin (HE)-stained slides were reviewed to confirm the diagnosis by one pathologist (T.E.). Pathology was confirmed as thymic carcinoma in 17 cases and thymoma in 20 cases. Patients

Results

Results of KIT expression by immunohistochemistry are shown in Table 3. KIT-positive staining was observed only in thymic carcinoma. The percentage of positive staining was 100% in squamous cell carcinoma, whereas other histologies including atypical carcinoids and thymoma showed no positive staining. Interestingly, in two cases of pulmonary metastasis from squamous cell carcinoma of the thymus, KIT expression was observed in both metastatic tumors. In one case, initial diagnosis of pulmonary

Discussion

This study demonstrated that squamous cell carcinoma of the thymus frequently expressed KIT protein, whereas other types of thymic tumor did not. These findings are in accordance with results reported by others. Henley et al. first examined expression of both KIT and EGFR in 21 thymomas and 4 thymic carcinomas [9]. They concluded that an EGFR-negative/KIT-positive staining pattern is typical of thymic carcinoma. Nakagawa et al. studied KIT and CD5 expression in thymic epithelial tumors and

Conflict of interest statement

There is no conflict of interest with regard to this manuscript.

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