Abstract
Purpose
Endocervical adenocarcinomas (ECA) and endometrial adenocarcinomas (EMA) are uterine malignancies that have differing biological behavior. The choice of appropriate therapeutic plan depends indeed on the tumor’s site of origin. In this study, we not only compare the individual expression status of five immunomarkers (ER, PR, Vim, CEA, and p16INK4a), but also evaluate whether p16INK4a adds value to the ER/PR/Vim/CEA panel characteristics in distinguishing between primary ECA and EMA.
Methods
A tissue microarray (TMA) was constructed using paraffin-embedded, formalin-fixed tissues from 35 hysterectomy specimens, including 14 ECA and 21 EMA. TMA sections were immunostained with five anti-bodies, by avidin–biotin complex (ABC) method for antigen visualization. The staining intensity and area extent of the immunohistochemical (IHC) reactions were appraised by using the semi-quantitative scoring system.
Results
The four respective markers (ER, PR, Vim, CEA) and their combined panel expressions showed significant (p < 0.05) frequency differences between ECA and EMA tumors. The p16INK4a marker also revealed a significant frequency difference (p < 0.05) between the two sites of origin, but did not demonstrate to have any supplementary value to the 4-marker panel.
Conclusion
According to our data, when there is histomorphological and clinical doubt as to the primary site of origin, we recommend that the conventional 4-marker (ER/PR/Vim/CEA) panel is appropriate. Ancillary p16INK4a-marker testing does not add value to the 4-marker panel in distinguishing between primary ECA and EMA.
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References
Luran JR (2007) Uterine cancer. Gynecology, Chap. 33, 14th edn. Berek & Novak, Philadelphia, pp 1343–1402
Bidus MA, Elkas JC (2007) Cervical and vagianl cancer. Gynecology, Chap. 34, 14th edn. Berek & Novak, Philadelphia, pp 1343–1402
Dabbs DJ, Sturtz K, Zaino RJ (1996) Distinguishing endometrial from endocervical adenocarcinoma. Hum Pathol 27(2):172–177
Castrillon DH, Lee KR, Nucci MR (2002) Distinction between endometrial, endocervical adenocarcinoma: An immunohistochemical study. Int J Gynecol Pathol 21(1):4–10
McCluggage WG, Sumathi VP, McBride HA, Patterson AA (2002) A panel of immunohistochemical stains, including carcinoembryonic antigen, vimentin, and estrogen receptor, aids the distinction between primary endometrial and endocervical adenocarcinomas. Int J Gynecol Pathol 21(1):11–15
Alkushi A, Irving J, Hsu F, Dupuis B, Liu CL, Rijn M, Gilks CB (2003) Immunoprofile of cervical and endometrial adenocarcinomas using a tissue microarray. Virchows Arch 442(3):271–277 [Epub 2003 Feb 12]
Zweig MH, Campbell G (1993) Receiver-Operating Characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 39(4):561–577
Metz CE (1978) Basic principles of ROC analysis. Semin Nucl Med 8(4):283–298
Remmele W, Schicketanz KH (1993) Immunohistochemical determination of estrogen, progesterone receptor content in human breast cancer. Computer-assisted image analysis (QIC score) vs. subjective grading (IRS). Pathol Res Pract 189(8):862–866
Matos LL, Stabenow E, Tavares MR, Ferraz AR, Capelozzi VL, Pinhal MA (2006) Immunohistochemistry quantification by a digital computer-assisted method compared to semiquantitative analysis. Clinics 61(5):417–424
Kamoi S, AlJuboury MI, Akin MR, Silverberg SG (2002) Immunohistochemical staining in the distinction between primary endometrial and endocervical adenocarcinomas: another viewpoint. Int J Gynecol Pathol 21(3):217–223
Khoury T, Tan D, Wang J, Intengan M, Yang J, Alrawi S, Yan P, Byrd JC (2006) Inclusion of MUC1 (Ma695) in a panel of immunohistochemical markers is useful for distinguishing between endocervical and endometrial mucinous adenocarcinoma. BMC Clin Pathol 6:1
Han CP, Lee MY, Tzeng SL, Yao CC, Wang PH, Cheng YW, Chen SL, Wu TS, Tyan YS, Kok LF (2008) Nuclear Receptor Interaction Protein (NRIP) expression assay using human tissue microarray and immunohistochemistry technology confirming nuclear localization. J Exp Clin Cancer Res 27:25
Camp RL, Chung GG, Rimm DL (2002) Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med 8(11):1323–1327 [Epub 2002 Oct 21]
Reid-Nicholson M, Iyengar P, Hummer AJ, Linkov I, Asher M, Soslow RA (2006) Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis. Mod Pathol 19(8):1091–1100 [Epub 2006 Apr 28]
Cregger M, Berger AJ, Rimm DL (2006) Immunohistochemistry and quantitative analysis of protein expression. Arch Pathol Lab Med 130(7):1026–1030
Revision B (2007) IHC nuclear image analysis user’s guide, MAN–0027, Jan 2007; Aperio, p 1–43. http://www.aperio.com/documents/XY_rel82/Aperio_IHC_Nuclear_Image_Analysis.pdf
Fregonesi PA, Teresa DB, Duarte RA, Neto CB, de Oliveira MR, Soares CP (2003) p16(INK4A) immunohistochemical overexpression in premalignant and malignant oral lesions infected with human papillomavirus. J Histochem Cytochem 51(10):1291–1297
Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, Shiraga S, Bainbridge T, Morich J, Heinrich MC (2005) PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23(23):5357–5364 [Epub 2005 May 31]
Powell EL, Leoni LM, Canto MI, Forastiere AA, Iocobuzio-Donahue CA, Wang JS, Maitra A, Montgomery E (2005) Concordant loss of MTAP and p16/CDKN2A expression in gastroesophageal carcinogenesis: evidence of homozygous deletion in esophageal noninvasive precursor lesions and therapeutic implications. Am J Surg Pathol 29(11):1497–1504
McCluggage WG, Jenkins D (2003) p16 immunoreactivity may assist in the distinction between endometrial and endocervical adenocarcinoma. Int J Gynecol Pathol 22(3):231–235
Vallmanya Llena FR, Laborda Rodríguez A, Lloreta Trull J, Cortadellas Angel R, Placer Santos J, Mas Gelabert A (2006) Immunohistochemical expression of p53, p21, p16, and cyclin D1 in superficial bladder cancer. A tissue microarray study. Actas Urol Esp 30(8):754–762
Milde-Langosch K, Bamberger AM, Rieck G, Kelp B, Löning T (2001) Overexpression of the p16 cell cycle inhibitor in breast cancer is associated with a more malignant phenotype. Breast Cancer Res Treat 67(1):61–70
Ranade K, Hussussian CJ, Sikorski RS, Varmus HE, Goldstein AM, Tucker MA, Serrano M, Hannon GJ, Beach D, Dracopoli NC (1995) Mutations associated with familial melanoma impair p16INK4 function. Nat Genet 10(1):114–116
Miettinen M, Sobin LH, Lasota J (2005) Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with longterm follow-up. Am J Surg Pathol 29(1):52–68
Huang HY, Huang WW, Lin CN, Eng HL, Li SH, Li CF, Lu D, Yu SC, Hsiung CY (2006) Immunohistochemical expression of p16INK4A, Ki-67, and Mcm2 proteins in gastrointestinal stromal tumors: prognostic implications and correlations with risk stratification of NIH consensus criteria. Ann Surg Oncol 13(12):1633–1644 [Epub 2006 Sep 30]
Kommoss S, du Bois A, Ridder R, Trunk MJ, Schmidt D, Pfisterer J, Kommoss F, the AGO-OVAR (2007) Independent prognostic significance of cell cycle regulator proteins p16(INK4a) and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group. Br J Cancer 96(2):306–313
Grayson W (2003) Mini-symposium: immunohistologyingynaecological pathology: application of immunohistochemistry in the evaluation of neoplastic epithelial lesions of the uterine cervix and endometrium. Curr Diagn Pathol 9:19–25. http://download.journals.elsevierhealth.com/pdfs/journals/0968-6053/PIIS0968605302901523.pdf
Miller RT (2003) Endocervical vs. endometrial adenocarcinoma: update on useful immunohistochemical markers, The FOCUS—Immunohistochemistry, 1–2 Apr 2003. http://ihcworld.com/_newsletter/2003/focus_apr_2003.pdf
Mittal K, Soslow R, McCluggage WG (2008) Application of immunohistochemistry to gynecologic pathology. Arch Pathol Lab Med 132(3):402–423
Acknowledgments
This work was supported in parts by grants from Department of Health, (DOH98-PAB-1001-E and DOH98-PAB-1009-I), and Chung-Shan Medical University Hospital, Taiwan, ROC.
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The authors declare that they have no conflict of interest.
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C.-C. Yao and L.-F. Kok have equally contributed to this article.
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Yao, CC., Kok, LF., Lee, MY. et al. Ancillary p16INK4a adds no meaningful value to the performance of ER/PR/Vim/CEA panel in distinguishing between primary endocervical and endometrial adenocarcinomas in a tissue microarray study. Arch Gynecol Obstet 280, 405–413 (2009). https://doi.org/10.1007/s00404-008-0859-1
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DOI: https://doi.org/10.1007/s00404-008-0859-1