Immunohistochemical evaluation of C-KIT expression in uterine carcinosarcomas

Öz

Objective: Carcinosarcoma is a very aggressive neoplasm. The use of tyrosine kinase inhibitors has resulted in successful treatment of KIT-positive neoplasms. Consequently, c-kit expression may have significant clinical implications for this tumor. The purpose of the present study was to assess c-kit expression in the carcinomatous and sarcomatous component of carcinosarcoma and to identify if KIT represents a therapeutic target for treatment of this neoplasm.

Material and Method: Immunohistochemical staining for c-kit was performed on paraffin-embedded tissue blocks of 20 uterine specimens with carcinosarcoma.

Results: In the stromal component of carcinosarcoma, no immunohistochemically c-kit stained cells were observed and in the epithelial component, c-kit staining was present in 9 cases.

Conclusion: The results seem to suggest that c-kit probably plays no major role in the carcinogenesis of the majority of these tumors. Further studies of c-kit expression in larger series of carcinosarcomas must be studied in order to clarify the controversial issues.

Anahtar Kelimeler

• uterus
• c-kit
• carcinosarcoma
• immuno- histochemistry

Uterin karsinosarkomlarda immunohistokimyasal olarak C-KIT ekspresyonunun değerlendirilmesi

Öz

Amaç: Karsinosarkom oldukça agresif bir neoplazmdır. KIT-pozitif neoplazmlarda tirozin kinaz inhibitörleri tedavide başarılı sonuçlar vermektedir. Bu nedenle, bu tümörlerde c-kit ekspresyonu klinik açıdan önemli olabilir. Bu çalışmanın amacı, karsinosarkomun karsinomatöz ve sarkomatöz komponenetlerinde c-kit ekspresyonunu incelemek ve bu neoplazmlarda KIT’in terapötik bir hedef olarak kullanılabilirliğini saptamaktır.

Gereç ve Yöntem: Karsinosarkom tanısı almış 20 uterusa ait parafine gömülü bloklara immunohistokimyasal olarak c-kit boyaması uygulandı.

Bulgular: Karsinosarkomların stromal komponentlerinde immunohistakimyasal olarak c-kit boyanan hücre saptanmadı, ve epitelyal komponenette ise 9 olguda c-kit boyaması mevcuttu.

Sonuç: Sonuçlar c-kit’in bu tümörlerin karsinogenezinde muhtemelen major bir rol oynamadığını destekler görünmektedir. Tartışmalı konuları açıklığa kavuşturmak için geniş serilerle yapılacak c-kit ekspresyonunu belirleyecek yeni çalışmalar gerekmektedir.

Anahtar Kelimeler

• uterus
• karsinosarkom
• c-kit
• immünohistokimya

Kaynakça

1. Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, et al. Human proto-oncogene kit, a new cell surface-receptor tyrosine kinase for unidentified ligand. EMBO J 1987;6:3341 – 51.
2. Williams DE, Eisenman J, Baird A, Rauch C, Van Ness K, March CJ, et al. Identification of a ligand for the c-kit proto-oncogene. Cell 1990;63:167 – 74.
3. d’Auriol L, Mattei MG, Andre C, Galibert F. Localization of the human c-kit protooncogene on the q11–q12 region of chromosome 4. Hum Genet 1988;78:374 – 6.
4. Nakata Y, Kimura A, Katoh O, Kawaishi K, Hyodo H, Abe K, et al. C-kit point mutation of extracellular domain in patients with myeloproliferative disorders. Br J Haematol 1995;91:6610 – 30.
5. Dudani S, Kalhan S, Sharma S, Gupta A. Gastrointestinal stromal tumours (GIST)-pathology and clinical applications of recent molecular advences-A perspective review. Çağdaş Tıp Dergisi 2014;4:85-90.
6. Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, et al. KIT activation is a ubiquitous feature of gastrointestinal stroma. Cancer Res 2001;61(22):8118 – 21.
7. Demetri GD. Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinibe mesylate (STI571) Eur J Cancer 2002;38 (Suppl 5):52–59.
8. Druker BJ, Sawyers CL., Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome N Engl J Med 2001;344:1038–42.

9. DeMatteo RP. The GIST of targeted cancer therapy: a tumor gastrointestinal stromal tumor), a mutated gene (c-kit), and a molecular nhibitor (STI571) Ann Surg Oncol 2002;9:831–3.
10. Demetri GD. Targeting c-kit mutations in solid tumors: scientific rationale and novel therapeutic options. Semin Oncol 2001;28 (Suppl 17):19–26.
11. Heinrich MC., Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol 2002;33:484–95.
12. Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to treatment of KIT-positive malignancies J Clin Oncol 2002;20:1692–703.
13. Elmore LW, Domson K, Moore JR, Kornstein M, Burks RT. Expression of c-kit (CD117) in benign and malignant human endometrial epithelium. Arch Pathol Lab Med 2001;125:146–51.
14. Scobie JV, Acs G, Bandera CA, Blank SV, Wheeler JE, Pasha TL, et al. C-kit immunoreactivity in endometrial adenocarcinomas and its clinicopathological significance. Int J Gynecol Pathol 2003;22:149–50.
15. Alkushi A, Irving J, Hsu F, Dupuis B, Liu CL, Rijn M, et al. Immunoprofile of cervical and endometrial adenocarcinomas using a tissue microarray Virchows Arch 2003;442: 271–7.
16. Winter WE III, Seidman JD, Krivak TC, ChauhanS, Carlson JV, Rose, GS et al. Clinicopathological analysis of c-kit expression in carcinosarcomas and leiomyosarcomas of the uterine corpus. Gynecol Oncol 2003;91:3–8.
17. Rushing RS, Shajahan S, Chendil D, Wilder JL, Pulliam J, Lee EY, et al. Uterine sarcomas express KIT protein but lack mutation(s) in exon 11 or 17 of c-KIT. Gynecol Oncol 2003;91:9–14.
18. Klein WM, Kurman RJ. Lack of expression of c-kit protein (CD117) in mesenchymal tumors of the uterus and ovary. Int. J Gynecol Pathol 2003;22:181–4.
19. Ramondetta LM, Burke TW, Jhingran A, Schmandt R, Bevers MV, Wolf JK, et al.A phase II trial of cisplatin, ifosfamide, and mesna in patients with advanced or recurrent uterine malignant mixed Mullerian tumors with evaluation of potential molecular targets. Gynecol Oncol 2003;90:529–36.
20. Huh WK, Conner MG, Straughn Jr. JM, Leath CA, Barnes MN, Alvarez RD, et al. Immunohistochemical evaluation of the c Kit proto-oncogene in sarcomas of the uterus. Gynecol Oncol 2002;84:531 [abstract].
21. Constantinescu M, Turbat-Herrera EA, Nordberg ML, et al. CD117 and CD34 expression by immunohistochemistry in uterine mixed Mullerian tumors Lab Invest 2003;83:186A–7A [abstract].
22. Sawada M, Tsuda H, Kimura M, Okamoto S, Kita T, Kasamatsu T, et al. Different expression patterns of KIT, EGFR, and HER-2 (c erbB-2) oncoproteins between epithelial and mesenchymal components in uterine carcinosarcoma. Cancer Sci 2003;94:986–91.
23. Leath CA III, Straughn Jr. JM, Conner MG, Barnes III MN, Alvarez RD, Partridge EE, et al. Immunohistochemical evaluation of the c-kit proto-oncogene in sarcomas of the uterus: a case series J Reprod Med 2004;49:71–5.
24. Gadducci A, Sartori E, Landoni F, Zola P et al. The prognostic relevance of histological type in uterine sarcomas: a Cooperation Task Force (CTF) multivariate analysis of 249 cases Eur. J. Gynecol. Oncol 2002;23:295–9.
25. Lucas DR, al-Abbadi M, Tabaczka P, Hamre MR, Weaver DW, Mott MJ. c-Kit expression in desmoid fibromatosis. Comparative immunohistochemical evaluation of two commercial antibodies Am. J. Clin. Pathol 2003;119:339–45.
26. Wang L, Felix JC, Lee JL, Tan PY, Tourgeman DE, O'Meara AT, et al. The proto-oncogene c-kit is expressed in leiomyosarcomas of the uterus. Gynecol. Oncol 2003;90:402–6.
27. Miettinen M, Sobin LH, Sarlomo-Rikala M. Immunohistochemical spectrum of GISTs at different sites and their differential diagnosis with reference to CD117 (KIT). Mod. Pathol 2000;13:1134–42.
28. Abargel a, Avinoach I, Kravtsov V, Boaz M, Glezerman M, Menczer J. Expression of p27 and p53: comparative analysis of uterine carcinosarcoma and endometrial carcinoma. Int. J. Gynecol. Cancer 2004;14: 354–9.
29. Bamberger A, Riethdorf L, Milde-Langosch K, Bamberger CM, Thuneke I, Erdmann I, et al. Strongly reduced expression of the cell cycle inhibitor in endometrial neoplasia Virchows Arch 1999;443:423–8.
30. Raspollini MR, Villanucci A, Amunni G, Paglierani M, TaddeiA, Taddei GL. C-kit expression in uterine leiomyosarcomas: an immunocytochemical study of 29 cases of malignant smooth muscle tumors of the uterus J. Chemother 2003;15:81–4.
31. McCluggage WG. Uterine carcinosarcomas (malignant mixed Mullerian tumors) are metaplastic carcinomas. Int. J. Gynecol. Cancer 2002;12:687–90.
32. Kounelis S, Jones MW, Papadaki P, Bakker A, Swalsky P, Finkelstein SD. Carcinosarcoma (malignant mixed Mullerian tumors) of the genital tract: comparative molecular analysis of epithelial and mesenchymal components. Hum. Pathol 1998;29:82–7.
33. Guarino M, Giordano F, Pallotti F, Polizzoti G, Tricomi P, Cristofori E. Malignant mixed Mullerian tumor of the uterus. Feature favoring its origin from a common cell clone and an epithelial to mesenchymal transformation of histogenesis. Tumori 1998;84:391–7.
34. Szukala SA, Marks JR, Burchette JL, Elbendery AA, Krigman HR. Co-expression of p53 by epithelial and stromal elements in carcinosarcoma of the female genital tract: an immunohistochemical study of 19 cases. In. J. Gynecol. Cancer 1999;9:131–6.
35. 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.