Ann Thorac Surg 2004;77:247-252
© 2004 The Society of Thoracic Surgeons
Original article: general thoracic
The prognostic role of c-kit protein expression in resected large cell neuroendocrine carcinoma of the lung
Christian Casali, MDa,
Alessandro Stefani, MDa,
Giulio Rossi, MDb,
Mario Migaldi, MD, PhDb,
Stefania Bettelli, BDScb,
Alessia Parise, MDa,
Uliano Morandi, MDa*
a Department of Surgical and Medical Specialties, Division of Thoracic Surgery, University of Modena and Reggio Emilia, Modena, Italy
b Department of Pathologic Anatomy and Forensic Medicine, Section of Pathology, University of Modena and Reggio Emilia, Modena, Italy
Accepted for publication July 8, 2003.
* Address reprint requests to Dr Morandi, Division of Thoracic Surgery, Policlinico di Modena, Largo del Pozzo 71, 41100 Modena, Italy.
e-mail: u.morandi{at}unimo.it
 |
Abstract
|
|---|
BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine tumor of the lung that shares some clinicopathologic and molecular features with small cell lung carcinoma (SCLC). Optimal treatment has not yet been standardized and significant prognostic factors are lacking. Because c-kit protein overexpression has been recently reported as a negative prognostic factor in SCLC we investigated its expression and prognostic value in a series of LCNEC.
METHODS: Resected LCNEC fulfilling the morphologic criteria of the 1999 World Health Organization classification of lung tumors and showing neuroendocrine differentiation by appropriate immunohistochemical markers were retrospectively reviewed. Immunostaining for c-kit protein expression was performed using the polyclonal antibody CD117. Clinical and pathologic characteristic were reported and analyzed and a survival study was performed.
RESULTS: Thirty-three patients underwent radical resection. Thirty-one were male (94%) and 32 were smokers (97%). Ten (30.3%), 11 (33.3%), 5 (15.2%), and 7 (21.2%) were at stage IA, IB, IIB, and IIIA respectively. Overall 1-, 3-, and 5-year survival rates were respectively 79%, 58%, and 51%. Survival analysis showed no differences for any of the clinicopathological features except for CD117 immunostaining: 1-year and 3-year survival rates were respectively 91% and 82% for CD117-negative LCNEC, and 72% and 44% for CD117-positive ones (p = 0.046). Positivity of CD117 was significantly related to recurrence rate: 60% versus 23% for CD117 positive and negative LCNEC respectively (p = 0.037).
CONCLUSIONS: Radical resection of large cell neuroendocrine carcinoma achieves poor outcomes. The c-kit protein is frequently expressed in this neoplasia and its expression represents a negative prognostic factor. This immunohistochemical marker may represent the basic rationale to select LCNEC for novel targeted therapy.
|
Introduction
|
|---|
Large cell neuroendocrine carcinoma (LCNEC) is a distinctive clinicopathologic entity that shows neuroendocrine morphology and differentiation. Diagnostic criteria for LCNEC were originally defined by Travis and colleagues [1] who subsequently proposed a three-grade scheme for pulmonary neuroendocrine tumors [2]: typical and atypical carcinoids are considered low- and intermediate-grade tumors respectively, and LCNEC together with small cell lung carcinoma (SCLC) is a high-grade neuroendocrine malignancy. Although this scheme has been definitely adopted by the 1999 World Health Organization classification of lung tumors [3], LCNEC is still considered a variant of large cell carcinoma thus belonging to the group of nonsmall cell lung carcinoma (NSCLC). However, LCNEC and SCLC share various pathologic findings [4] and molecular features [5, 6]. Moreover from a clinical standpoint several authors reported poor outcomes for surgically resected LCNEC with survival rates that are more similar to SCLC than to NSCLC [1, 2, 7–14].
Recently, Micke and associates [15] showed that c-kit protein overexpression had a negative prognostic impact in SCLC. This protein is the product of the proto-oncogene c-kit, encoding a cell-surface tyrosine kinase that acts as growth factor receptor. Its activation mediated by the relevant ligand, stem cell factor, promotes tumor cell proliferation and blocks apoptosis in different malignancies including SCLC [16]. To date no prognostic factors have been investigated to ascertain which LCNEC are at high risk of relapse or likely to have an aggressive clinical course after radical surgery. Given the close relationship between SCLC and LCNEC in this study, we analyzed the expression of c-kit protein in a series of resected LCNEC with reference to its possible prognostic role.
|
Material and methods
|
|---|
Files from the archives of the Section of Pathology of the University of Modena and Reggio Emilia were retrospectively reviewed to retrieve all patients with LCNEC of the lung who underwent surgical resection at the Division of Thoracic Surgery between January 1993 and December 2002. The original histologic diagnoses selected for this review included atypical carcinoids, large cell undifferentiated carcinomas, basaloid carcinomas, poorly differentiated adenocarcinomas, poorly differentiated squamous cell carcinomas, and small cell carcinomas. According to the 1999 WHO morphologic criteria [3] tumors were reclassified as LCNEC if they fulfilled the following criteria: (a) neuroendocrine morphology at light microscopy (organoid nesting, trabecular growth pattern, rosette-like structures, and nuclear palisading); (b) high mitotic rate, greater than 11 mitoses per 10 high-power fields (2 mm2); (c) presence of necrosis (centrilobular or in form of large areas); (d) cytologic features of nonsmall cell lung carcinoma (large cell size with a moderate amount of eosinophilic cytoplasm, vesicular, or fine nuclear chromatin with several nucleoli); and (e) immunoreactivity for at least one of the following neuroendocrine markers: chromogranin A, synaptophysin, and neural cell adhesion molecule (NCAM/CD56). Among 124 cases originally collected, 36 fulfilled the above morphologic and immunohistochemical criteria.
In the surgical specimens examined in this study, the neoplastic tissues were routinely fixed in 10% buffered-formalin and then paraffin embedded. A mean of 5.5 (range, 3 to 10) hematoxylin-eosin stained slides for tumor were available for histologic examination. All the slides were reviewed by two pathologists of our group (G.R., M.M.). A representative case of LCNEC is shown in Figure 1. Neuroendocrine differentiation was then confirmed by means of immunohistochemistry using the three following neuroendocrine markers: chromogranin A (clone DAK-A3; Dako, Glostrup, Denmark; 1:100 dilution), synaptophysin (clone SY38; Dako; 1:200 dilution), and NCAM/CD56 (clone 123C3; NeoMarkers, Fremont, CA; 1:100 dilution). In LCNEC immunohistochemical analysis was also performed for CD117 (A4502; Dako; 1:200 dilution), the specific policlonal antibody against c-kit protein. For immunohistochemical analysis 4-µm thick sections were obtained from a representative formalin-fixed, paraffin-embedded block. The sections were air dried at 37°C then deparaffinized in xylene and rehydrated through a decreasing alcohol-water concentration. Endogenous peroxidase activity was blocked by immersion in a solution of 3% hydrogen peroxide in methanol. For chromogranin A, synaptophysin, and NCAM/CD56 a microwave antigen retrieval was performed in 0.01 mol/L citrate buffer (pH 7.8). Antigen retrieval was not used for CD117. Incubation with the primary antibodies was accomplished with a modified avidin-biotin peroxidase technique using a commercial immunohistochemical autostainer (Ventana, Strasbourg, France); 3'-3diaminobenzidine was used as the chromogene and Harris' hematoxylin as the counterstain. Appropriate positive control sections were assessed in each test while negative controls were included in each test by substitution of the primary antibodies with nonimmune mouse IgG. For each antibody the percentage of positive cells (0 = negative; 1+ = 1% to 25%; 2+ = 26% to 50%; 3+ = > 50%) and the intensity of staining (0 = negative; 1 = weak; 2 = moderate; 3 = strong) were recorded. Immunohistochemical neuroendocrine markers were considered positive if more than 10% of neoplastic cells reacted with an intensity of 2+ or greater on the relevant subcellular localization (cytoplasmatic for chromogranin A and synaptophysin; cytoplasmatic and membranous for NCAM/CD56). The CD117 immunostaining was considered positive if at least 50% of tumor cells reacted with an intensity of at least 2+ on the appropriate subcellular localization (cytoplasm and membrane with or without paranuclear dot-like staining). Figure 2
shows a CD117-positive LCNEC. Tumors displaying all the other combinations of staining in regard to intensity and percentage of tumor cells were considered as negative.
View larger version (157K):
[in this window]
[in a new window]
|
Fig 1. Photomicrograph of a large cell neuroendocrine carcinoma of the lung. The tumor typically appears as a large cell carcinoma with organoid growth pattern, showing peripheral nuclear palisading, rosette-like structures, many mitotic figures, and large areas of necrosis. (Hematoxylin & eosin, original magnification x200.)
|
|
View larger version (157K):
[in this window]
[in a new window]
|
Fig 2. Photomicrograph of a large cell neuroendocrine carcinoma expressing c-kit protein. The specific immunohistochemical marker CD117 strongly stains the tumor cell membrane. (CD117 immunostaining, original magnification x200.)
|
|
The patients who underwent surgery for LCNEC represent the population of this study. Their clinical data were collected from medical records and clinical charts. The following clinical and pathologic features were recorded: age, sex, smoking history, surgical procedure, size of the primary tumor and pathologic staging, expression of chromogranin A, synaptophysin, NCAM/CD56 and c-kit protein, postoperative morbidity and mortality, and neoadjuvant and adjuvant therapies. All the patients were staged according to the revised TNM classification [17]. Complete resection was defined as removal of the primary tumor and all accessible hilar and mediastinal lymph nodes with no residual neoplastic tissue left. All the patients underwent complete tumor resection coupled to a complete mediastinal lymph node dissection. Incomplete resections were excluded from the study. Induction chemotherapy and adjuvant chemotherapy or radiation therapy or both were performed in some cases. Many different regimens of therapies were administered; that was because we investigated patients coming from different oncologic institutes over a long period of time. Because of this heterogeneity of treatment, chemotherapy and radiation therapy were not analyzed in this work.
Follow-up
Most patients were directly followed up at our institution with periodic office visits. Information about the remaining patients was obtained from the oncologic institutes to which the patients were referred or by telephone interviews with the patient or relatives. Data regarding mid- and long-term survival and presence and type of recurrence were recorded.
Statistical analysis
The descriptive analysis was expressed in terms of the frequency, mean, and standard deviation. Frequencies were compared with the 
2 test for categorical variables; Fisher's exact test was used for small samples; the phi correlation index was reported when a significant difference was found. The t test and analysis of variance (ANOVA) were performed when comparing continuous variables. The probability of survival was calculated according to the Kaplan-Meier method; when creating survival curves, deaths from causes other than the tumor and postoperative deaths were considered as withdrawals, the date of death representing the endpoint of follow-up. Resulting curves were compared by the log-rank test. The main prognostic factors were matched in a multivariate analysis using Cox regression models. A probability value less than 0.05 was considered statistically significant.
|
Results
|
|---|
Among the 124 selected cases, 36 strictly exhibited the pathologic criteria and were thus defined as LCNEC. Three patients underwent incomplete resection and were excluded from the study. Thus the present case series consists of 33 patients. Their clinicopathologic data were recorded and submitted to statistical analysis. Clinical and pathologic features of the patients are listed in Table 1. Mean age was 63.5 years (median, 65; SD 9.34; range, 42 to 80). Mean size of the primary tumor was 4.13 cm (median, 4.0; SD 1.72; range, 1.7 to 8.0 cm). Mean mitotic rate was 75 mitoses x 10 high-power fields (median, 76; SD 7.31; range, 65 to 98). Seven patients underwent limited pulmonary resections because of functional impairment. However in all these patients as well as in patients who underwent major pulmonary resections, a complete lymph node dissection was performed. There were 2 postoperative deaths (6%), both after lobectomies, due to adult respiratory distress syndrome and acute myocardial infarction respectively. Seven patients (21%) suffered from postoperative complications: empyema (n = 2), prolonged air leak (n = 4), andpneumonia (n = 1).
Sex and smoking history were excluded from our analysis because the difference in the frequencies of the two variables was too great. Given the relatively small case, series variables were modified as follows: with regard to type of resection, lobectomies and bilobectomies were grouped; with regard to pN-status, N1 and N2 were grouped; with regard to tumor stage, IA and IB were grouped and IIB and IIIA were also grouped. We matched all the clinicopathologic variables in a univariate analysis but no association was found among them. In particular no differences were found between the two categories of c-kit expression (CD117 positive versus CD117 negative) regarding age, size of the tumor (in centimeters), surgical procedure, pT-status, pN-status, pathologic stage, and postoperative morbidity.
Follow-up was complete for all patients up to January 2003 and ranged from 2 to 118 months (mean, 33.8; median, 24.9). The overall 1-, 3-, and 5-year survival rates were respectively 79%, 58%, and 51% (SE 7.5%, 9.2%, 10.5% respectively). Six patients (18%) are alive and well without recurrence more than 5 years after operation. Thirteen patients (39%; 2 postoperative deaths were excluded) died during follow-up because of recurrence of the primary tumor. Fifteen patients relapsed (45%): 13 had distant metastases and 2 had locoregional recurrence; 2 patients are alive with brain recurrence 33 and 37 months after operation. The univariate analysis showed no differences in survival rates for type of resection, pT-status, pN-status, pathologic stage, and expression of synaptophysin or chromogranin A. Results are listed in Table 2.
The analysis showed a significant impact of c-kit expression upon prognosis (Fig 3),
with a more favorable outcome for patients with negative CD117 (Table 2). Two patients (2 of 13; 15%) died in the c-kit negative group and 11 patients (11 of 20; 55%) died in the c-kit positive group, a significant difference (p = 0.023, phi index 0.39). When considering age, type of resection, size of the tumor, pN-status, expression of synaptophysin, chromogranin A, and c-kit in a multivariate Cox regression model, none of the above was found as a significant prognostic factor even if a trend toward significance was observed for c-kit (Table 3).
Tumors negative for CD117 had significantly lower rates of recurrence compared with positive ones (23% versus 60% respectively; p = 0.037, phi index 0.36). No other clinicopathologic variable showed correlation with recurrence rates.
View larger version (15K):
[in this window]
[in a new window]
|
Fig 3. Survival curves by the polyclonal antibody marker CD117. Large cell neuroendocrine carcinoma with CD117 positivity (dashed line) shows a significantly poorer survival (log-rank 2 3.97; p = 0.046) compared with large cell neuroendocrine carcinoma with CD117 negativity (solid line).
|
|
|
Comment
|
|---|
According to the 1999 WHO classification of lung tumors [3], LCNEC and SCLC represent high-grade entities among neuroendocrine malignancies. Small cell lung cancer is clinically considered a highly aggressive tumor whereas the biologic behavior as well as the optimal treatment of LCNEC are not completely clarified.
From a clinical standpoint previous studies reported a poor 5-year survival rate for resected LCNEC ranging from 13% to 57% (Table 4).
Our data confirm these figures: surgically treated LCNEC have a dismal outcome with an overall 5-year survival rate of 51%. Some of these studies adopted different classification schemes as regards the mitotic rate in lung neuroendocrine tumors or analyzed large cell carcinoma with clear-cut neuroendocrine features at morphology but neuroendocrine differentiation was not detected in all cases [7–10]. It is important to note that our population is more homogeneous and presents large cell carcinomas that exhibit both neuroendocrine morphology and neuroendocrine differentiation by appropriate immunohistochemical markers, as suggested by the 1999 WHO classification. Our study also showed that surgically treated LCNEC at early stages had a poor outcome. In 2002 Takei and associates [12] analyzed the largest series of resected LCNEC (87 cases) strictly exhibiting WHO diagnostic criteria and confirmed that LCNEC have a dismal prognosis even at early stages. As previously reported [11, 12] the aggressive clinical behavior of LCNEC is also underlined by the high frequency of systemic relapse after radical resection even at early stages.
These findings suggest that the clinical course of LCNEC closely resembles that observed in SCLC. These two high-grade neuorondocrine tumors also share various molecular markers and genetic abnormalities. Przygodzki and colleagues [5] found high expression of p53, k-ras-2, and C-raf-1 in both high-grade neuroendocrine tumors. In addition Onuki and colleagues [6] observed similar p53 gene mutations and loss of heterozygosity in various chromosomal regions in both LCNEC and SCLC. Jiang and coworkers [18] showed that bcl-2 protein expression was closely associated with high-grade neuroendocrine carcinomas but not with other histologic types of lung cancer. All these data lead us to consider LCNEC more similar to SCLC than to NSCLC.
At the moment there is little consesus on the optimal therapeutic strategy for LCNEC. Although surgery remains the best procedure for resectable tumors the results of surgical resection alone are unsatisfactory and a multimodality therapy is advisable even at early stages as in SCLC [19]. Iyoda and associates [20] found that adjuvant chemotherapy with cisplatin-based regimens improved survival but only at early stages. In our series 12 patients were treated with adjuvant chemotherapy or radiation therapy. The retrospective design of our study and the different therapeutic regimens did not allow a reliable statistical analysis of this variable.
The prognostic role of neuroendocrine differentiation has been largely investigated in NSCLC with different results [9, 21, 22]. In our series no correlation was found between the number or the types of neuroendocrine markers and recurrence rate or survival. To date no reliable prognostic factors have been found for patients with LCNEC.
Recently c-kit protein overexpression has been reported as a negative prognostic factor in SCLC in particular in patients with advanced disease and poor response to chemotherapy [15]. This protein, the product of the proto-oncogene c-kit, is a tyrosine kinase growth factor receptor regulating the normal development of different cell lines and also promoting tumor cell proliferation and blocking apoptosis in some hematopoietic disorders and solid malignancies [16]. When stimulated by its ligand, stem cell factor, or when constitutionally activated by mutation, c-kit protein triggers a cascade of intracytoplasmic signals inducing cell growth [16]. Approximately 70% of SCLC cell lines and tumor specimens express both c-kit receptor and its ligand, suggesting an autocrine/paracrine loop [22]. We investigated the expression of c-kit protein in LCNEC by its relevant immunohistochemical marker CD117. In our series CD117 was positive in 20 patients with 33 LCNEC (61%), as previously noted in SCLC. There is no correlation between CD117 positivity and pathologic stage, the marker being positive even at early stages, in nodes that are negative, and in small-sized LCNECs. The analysis showed a significantly worse survival rate for CD117 positive LCNEC and a correlation between CD117 positivity and relapse after surgery. Despite the small population analyzed in our study the statistical significance achieved for c-kit expression suggests a strong correlation between CD117 positivity and survival. More recently Araki and colleagues [23] confirmed that c-kit expression in LCNEC is similar to that observed in SCLC (55% of 40 resected LCNEC). By contrast they did not find any significant correlation between c-kit expression and the common clinicopathologic indicators and survival. However 29 of 40 LCNEC in their series were in stage I and displayed an unexpectedly good survival rate. It is noteworthy that our study as well as that by Araki and colleagues suggest that c-kit protein is abnormally expressed and certainly plays an important biological role in LCNEC. In fact c-kit protein is not detected in normal lung parenchyma. As in SCLC, patients with LCNEC that overexpresses c-kit could represent a selected population to be enrolled in future therapeutic trials adopting selective tyrosine kinase inhibitor such as imatinib mesylate (formerly STI571) [24]. This is a small molecule acting as tyrosine kinase inhibitor by blocking c-kit phosphorilation and activation. It has also been found effective in chronic myeloid leukemia and in gastrointestinal stromal tumors [24]. Several studies have observed an in vitro inhibitory effect of STI571 in SCLC cell lines [25, 26]. Whether c-kit protein in LCNEC is to be related to a constitutional mutation as shown in GIST or represents the expression of one of the main molecular mechanisms implied in the tumorigenesis of this tumor, it requires c-kit locus analysis.
In conclusion LCNEC is a relatively uncommon high-grade tumor characterized by clear-cut neuroendocrine differentiation. Despite complete resection it is associated with a dismal outcome and high rates of systemic recurrence even at early stages. As in SCLC the c-kit receptor is significantly overexpressed in LCNEC and its positivity seems to be significantly related to poor survival. Although further studies on larger series of LCNEC are needed this marker can identify selected patients who could receive some benefits from a multimodality treatment or alternative targeted therapies. [27]
|
References
|
|---|
- Travis W.D., Linnoila I.R., Tsokos M.G., et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical and flow cytometric study of 35 cases. Am J Surg Pathol 1991;15:529-553.[Medline]
- Travis W.D., Rush W., Flieder D.B., et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998;22:934-944.[Medline]
- World Health Organization. Histological typing of lung and pleural tumours, 3rd ed Berlin: Springer-Verlag, 1999.
- Marchevsky A.M., Gal A.A., Shah S., et al. Morphometry confirms the presence of considerable nuclear size overlap between "small cells" and "large cells" in high-grade pulmonary neuroendocrine neoplasm. Am J Clin Pathol 2001;116:466-472.[Abstract/Free Full Text]
- Przygodzki R.M., Finkelstein S.D., Langer J.C., et al. Analysis of p53, k-ras-2, and C-raf-1 in pulmonary neuroendocrine tumours. Correlation with histological subtype and clinical outcome. Am J Pathol 1996;148:1531-1541.[Abstract]
- Onuki N., Wistuba I.I., Travis W.D., et al. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer 1999;85:600-607.[Medline]
- Iyoda A., Hiroshima K., Toyozaki T., et al. Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology. Cancer 2001;91:1992-2000.[Medline]
- Dresler C.M., Ritter J.H., Patterson A., et al. Clinical-pathologic analysis of 40 patients with large cell neuroendocrine carcinoma of the lung. Ann Thorac Surg 1997;63:180-185.[Abstract/Free Full Text]
- Iyoda A., Hiroshima K., Baba M., et al. Pulmonary large cell carcinomas with neuroendocrine features are high-grade neuroendocrine tumors. Ann Thorac Surg 2002;73:1049-1054.[Abstract/Free Full Text]
- Jiang S.X., Kameya T., Shoji M., et al. Large cell neuroendocrine carcinoma of the lung. A histologic and immunoistochemical study of 22 cases. Am J Surg Pathol 1998;22:526-537.[Medline]
- Mazieres J., Daste G., Molinier L., et al. Large cell neuroendocrine carcinoma of the lung: pathological study and clinical outcome of 18 resected cases. Lung Cancer 2002;37:287-292.[Medline]
- Takei H., Asamura H., Maeshima A., et al. Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighty-seven cases. J Thorac Cardiovasc Surg 2002;124:285-292.[Abstract/Free Full Text]
- Garcia-Yuste M., Matilla J.M., Alvarez-Gago T., et al. Prognostic factors in neuroendocrine lung tumours: a Spanish multicentre study. Ann Thorac Surg 2000;70:258-263.[Abstract/Free Full Text]
- Zacharias J., Nicholson A.G., Ladas G., et al. Large cell neuroendocrine carcinoma and lage cell carcinomas with neuroendocrine morphology of the lung: prognosis after complete resection and systematic nodal dissection. Ann Thorac Surg 2003;75:348-352.[Abstract/Free Full Text]
- Micke P., Basray M., Faldum A., et al. Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications. Clin Cancer Res 2003;9:188-194.[Abstract/Free Full Text]
- Heinrich M.C., Blanke C.D., Druker B.J., 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]
- Mountain C.F. Revision in the international system for staging lung cancer. Chest 1997;111:1710-1717.[Abstract/Free Full Text]
- Jiang S.X., Kameya T., Sato Y., et al. Bcl-2 protein expression in lung cancer and close correlation with neuroendocrine differentiation. Am J Pathol 1996;148:837-846.[Abstract]
- Shepherd F.A., Evans W.K., Feld R., et al. Adjuvant chemotherapy following surgical resection of small cell lung cancer. J Clin Oncol 1988;6:832-838.[Abstract/Free Full Text]
- Iyoda A., Hiroshima K., Toyozaki T., et al. Adjuvant chemotherapy for large cell carcinoma with neuroendocrine features. Cancer 2001;92:1108-1112.[Medline]
- Schleusener J.T., Tazelaar H.D., Jung S.H., et al. Neuroendocrine differentiation is an independent prognostic factor in chemotherapy-treated non small cell lung carcinoma. Cancer 1996;777:1284-1291.
- Harada M., Yokose T., Yoshida J., et al. Immunohistochemical neuroendocrine differentiation is an independent prognostic factor in surgically resected large cell carcinoma of the lung. Lung Cancer 2002;38:177-184.[Medline]
- Araki K., Ishii G., Yokose T., et al. Frequent overexpression of the c-kit protein in large cell neuroendocrine carcinoma of the lung. Lung Cancer 2003;40:173-180.[Medline]
- Hibi K., Takahashi T., Sekido Y., et al. Coexpression of stem cell factor and the c-kit genes in small cell lung cancer. Oncogene 1991;6:2291-2296.[Medline]
- Savage D.G., Antman K.H. Imatinib mesylate—a new oral targeted therapy. N Engl J Med 2002;28:683-693.
- Wang W.L., Healy M.E., Sattler M., et al. Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by novel tyrosine kinase inhibitor STI571. Oncogene 2000;19:3521-3528.[Medline]
- Krystal G.W., Honsawck S., Litz J., et al. The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth. Clin Cancer Res 2000;6:3319-3326.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
A. Iyoda, K. Hiroshima, Y. Nakatani, and T. Fujisawa
Pulmonary Large Cell Neuroendocrine Carcinoma: Its Place in the Spectrum of Pulmonary Carcinoma
Ann. Thorac. Surg.,
August 1, 2007;
84(2):
702 - 707.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K Sato, R Waseda, Y Tatsuzawa, H Fujinaga, T Wakabayashi, Y Ueda, and S Katsuda
Composite large cell neuroendocrine carcinoma and adenocarcinoma of the common bile duct
J. Clin. Pathol.,
January 1, 2006;
59(1):
105 - 107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Rossi, A. Cavazza, A. Marchioni, L. Longo, M. Migaldi, G. Sartori, N. Bigiani, L. Schirosi, C. Casali, U. Morandi, et al.
Role of Chemotherapy and the Receptor Tyrosine Kinases KIT, PDGFR{alpha}, PDGFR{beta}, and Met in Large-Cell Neuroendocrine Carcinoma of the Lung
J. Clin. Oncol.,
December 1, 2005;
23(34):
8774 - 8785.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
