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Journal of Clinical Oncology, Vol 23, No 22 (August 1), 2005: pp. 5268-5271 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.3409
Prevalence of KIT Expression in Human Tumors: Gallbladder CancerGrupo de Estudio, Tratamiento, e Investigación del Cáncer del Sur (GETICS), and Hospital Privado Santa Clara de Asís, Salta, Argentina
San Isidro Patología, Buenos Aires, Argentina
Hospital Privado Santa Clara de Asís, Salta, Argentina
Laboratorio Privado de Patología, Salta, Argentina
Servicio Privado de Patología, Salta, Argentina
Thywill Latam Solutions SRL (formerly Novartis Argentina SA), Buenos Aires, Argentina. To the Editor:
We read with great interest the article by Went et al,1 especially the results concerning gallbladder cancer (GC) where none of the 27 samples expressed the KIT protein. GC is a major problem in the province of Salta in northwestern Argentina, where the annual mortality rate was 7.3 per 100,000 persons in 1997-2001, being the third leading cause of death from cancer in women.2 This is in contrast to the statistics in industrialized countries. In the United States, the incidence rate is 2.5 cases per 100,000 persons.3 Because new therapies are required for GC, which has a five-year survival rate near 0%, and because it has been shown that cells that are progenitors of bile ducts are KIT positive4,5 and bile ducts from adults include cells which express KIT,6 we looked for the expression of KIT in GC samples from our area.7 After the histologic diagnosis was reviewed by three independent pathologists, 50 samples were selected for which the reviewers were in full agreement about the diagnosis. Sections (4 to 5 µm) from at least one representative block of each case were deparaffinized, rehydrated in graded alcohols, and subjected to microwave unmasking in 0.1 M citrate buffer (pH6) for 15 minutes. In accordance with manufacturer guidelines, the slides were then incubated with primary antibody anti-CD117 (polyclonal 1:250, DAKO; Carpinteria, CA) overnight. Localization was performed via the standard avidin-biotin immunoperoxidase method (ABC-VECTOR) with nickel chloride–enhanced 3,3'-diaminobenzidine (DAB) chromogen. After this step was performed, slides were counterstained with hematoxilin. Multiple fields were examined and the results expressed semiquantitatively. Each slide was scored from 0 (no staining) to 3 (strong staining) based on intensity, and was scored as focal (< 10% of cells), moderate (11% to 50% of cells) or diffuse (more than 50% of cells), based on percentage of stained cells. Results are listed in Tables 1 and 2 . Examples of different staining results are shown in Figure 1. As has been our experience in the clinic, the majority of the samples belonged to women older than 50 years. Forty-seven samples (94%) stained negative. Three samples (6%) stained positive focally (< 10% of cells) with a 3+ score. One sample was a poorly differentiated adenocarcinoma with papillary extensions. Another was a poorly differentiated adenocarcinoma. The third was a large cell undifferentiated GC sample. Three (21%) of 14 poorly differentiated and undifferentiated samples expressed the KIT protein. Because all of the positively stained samples were poorly differentiated or undifferentiated cancers, we tested the hypothesis that the degree of differentiation correlated to KIT expression using the
KIT was not expressed in 94% of the samples. One study from the United States reported a similar analysis with opposite results. Aswad et al8 studied 15 specimens of hepatoma, which stained negative for the KIT protein and 12 samples of bile duct and gallbladder adenocarcinomas, seven of which (58%) showed weak or moderate KIT expression. It is possible that KIT protein is expressed in bile duct cancers and not in gallbladder adenocarcinoma. Aswad et al did not report these results separately. It is also possible that the different results are explained by the role of chance since the authors analyzed fewer than 12 GC samples. Our results are in agreement with the results in the Went et al article.1 Although we found that 21% (three of 14) of the poorly differentiated and undifferentiated tumors expressed the KIT protein, raising the hypothesis of a subgroup of tumors with a particular pathogenetic pathway, staining was focal (< 10% of cells) in the three specimens and this argues against a possible therapeutic role of a KIT inhibitor even in this subgroup of tumors. Although neither Went et al nor our group found KIT expression in GC, we cannot affirm that imatinib has no therapeutic role in this disease. Merchant et al9 showed that imatinib interferes with the growth of Ewing's sarcoma cell lines in vivo but at a much higher dose than the one required to inhibit KIT. In contrast, the hypereosinophilic syndrome is highly responsive to very low doses of imatinib which produced minimal responses in Chronic Myelogenous Leukemia.10,11 Therefore, based on our results and those from Went et al, we cannot rule out the possibility that imatinib mesylate is useful as a therapeutic strategy for GC. As mentioned by Went et al, it could inhibit another tyrosine kinase that would be important for cell growth. In order to test this or similar hypotheses, it would be necessary to study the effect of imatinib mesylate at different concentrations in GC cell lines. However, based on current results, a trial with imatinib as a KIT inhibitor in GC is not warranted. Authors' Disclosures of Potential Conflicts of Interest Although all authors have completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) <$10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Went PT, Dirnhofer S, Bundi M, et al: Prevalence of KIT expression in human tumors. J Clin Oncol 22:4514-4522, 2004 2. Matos EL, Loria DI, Zengarini N, et al: Atlas de mortalidad por cáncer en Argentina 1997-2001 [in Spanish]. Buenos Aires, Argentina, Bunge y Born Foundation, 2003
3. Landis SH, Murray T, Bolden S, et al: Cancer statistics 1999. CA Cancer J Clin 49:8-31, 1999 4. Crosby HA, Kelly DA, Strain AJ: Human hepatic stem-like cells isolated using KIT or CD34 can differentiate into biliary epithelium. Gastroenterology 120:534-544, 2001[CrossRef][Medline] 5. Baumann U, Crosby HA, Ramani P, et al: Expression of the stem cell factor receptor KIT in normal and diseased pediatric liver: Identification of a human hepatic progenitor cell? Hepatology 30:112-117, 1999[CrossRef][Medline] 6. Fujio K, Hu Z, Evarts RP, et al: Coexpression of stem cell factor and KIT in embryonic and adult liver. Exp Cell Res 224:243-250, 1996[CrossRef][Medline] 7. Arroyo GF, Acosta G, Monteros Alvi M, et al: KIT expression in gallbladder cancer. Proc Am Soc Clin Oncol 22:303, 2003 (abstr 1215) 8. Aswad B, Constantinou M, Iannitti D, et al: KIT is a potential therapeutic target for biliary carcinomas. Proc Am Soc Clin Oncol 21:103b, 2002 (abstr 2227)
9. Merchant MS, Woo CW, Mackall CL, et al: Potential use of imatinib in Ewing's sarcoma: Evidence of in vitro and in vivo activity. J Natl Cancer Inst 94:1673-1679, 2002 10. Gleich GJ, Leiferman KM, Pardanani A, et al: Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet 359:1577-1578, 2002[CrossRef][Medline]
11. Druker BJ, Sawyers CL, Kantarjian H, et al: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031-1037, 2001
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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2 test. We found that both variables are not independent (P < .01). 
$100,000 (N/R) Not Required
