Histological and Immunohistochemical Evaluation of Cytokeratin 5/6 Expressing Breast Cancer
Introduction. Breast cancer represents morphologically, molecularly and prognostically heterogeneous group of tumours. In order to characterise the prognosis more exactly, molecular subtyping has been developed. However, the role of basal markers, including cytokeratin 5/6, (CK5/6) in the immunohistochemical typing of breast cancer still causes significant controversy.
Aim of the study was to determine the frequency of CK5/6 expression in invasive breast cancers in Latvian patients and to characterize CK5/6 positive tumours by histology and molecular subtypes in order to clarify the diagnostic role of CK5/6 expression in breast cancer.
Materials and methods: Consecutive potentially radically operated invasive breast cancer cases were identified by archive search. The gross and microscopic evaluation was performed on breast cancer protocol basis, aiming at complete description of morphological prognostic factors. Expression of oestrogen (ER) and progesterone (PR) receptors, actin, p53, p63, CK5/6 and Ki-67 was performed by immunohistochemistry. HER2 protein over-expression was detected by HercepTestTM. Molecular subtypes (luminal A, luminal B, HER-2 positive or triple negative) were determined for each tumour using ER, PR, HER-2 expression data. Descriptive statistics including calculation of 95% confidence interval (CI) was carried out by CIA software.
Results: Positive CK5/6 expression in tumour cells was observed in 23 (15.9%) cases [95% CI = 10.8-22.7]. No statistically significant differences were found between CK 5/6 positive cases and CK 5/6 negative controls regarding the histological type and grade of breast cancer as well as age of cancer diagnostics. CK 5/6 positive cases mostly were of luminal A (47.8%; 95% CI = 29.2-67.0) or triple negative (43.5%; 95% CI = 25.6-63.3) molecular subtype. CK5/6 expression was found in 43.4 % [95% CI = 25.6-63.1] of triple negative breast cancer cases in contrast to the expression rate 10.7% [95% CI = 6.3-17.3] in other molecular subtypes.
Conclusions: Frequency of CK5/6 expression is sufficient to carry out the diagnostic examination. CK 5/6 expression is not limited to single molecular type. Luminal A and triple negative breast cancer constitute the largest groups within CK5/6 positive cases. CK5/6 expression is significantly more frequent in triple negative breast cancer than in other molecular types. However, CK5/6 as a complementary marker for triple negative breast cancer is characterised by low sensitivity although high specifity. CK5/6 positive tumours tend to have higher proliferation fraction.
Altman D, Machin D, Bryant T, Gardner S. Statistics with confidence: confidence interval and statistical guidelines // 2nd edition, Bristol: BMJ Books, 2000
Awadelkarim KD, Arizzi C, Elamin EOM, Hamad HMA, De Blasio P, Mekki SO, Osman I, Biunno I, Elwali NE, Barberis MC, Mariani-Costantini R. Basal-Like Phenotype in a Breast Carcinoma Case Series from Sudan: Prevalence and Clinical/Pathological Correlations // Patholog Res Int, 2011; 2011: 1-10
Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, Cheang MC, Gelmon K, Nielsen TO, Blomqvist C, Heikkila P, Heikkinen T, Nevanlinna H, Akslen LA, Begin LR, Foulkes WD, Couch FJ, Wang X, Cafourek V, Olson JE, Baglietto L, Giles GG, Severi G, McLean CA, Southey MC, Rakha E, Green AR, Ellis IO, Sherman ME, Lissowska J, Anderson WF, Cox A, Cross SS, Reed MWR, Provenzano E, Dawson SJ, Dunning AM, Humphreys M, Easton DF, Garcia-Closas M, Caldas C, Pharoah PD, Huntsman D. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10159 cases from 12 Studies // PLoS Med, 2010; 7:1-12
Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MCU, Nielsen TO, Moorman PG, Earp HS, Millikan RC. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study // JAMA, 2006; 295:2492-2502
Choo JR, Nielsen TO. Biomarkers for Basal-like Breast Cancer // Cancer, 2010; 2:1040-1065
Colozza M, Azambuja E, Cardoso F, Sotiriou C, Larsimont D, Piccart MJ. Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now? // Ann Oncol, 2005; 16:1723-1739
Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn H-J & Panel members. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009 // Ann Oncol, 2009; 20:1319-1329
Koker MM, Kleer CG. p63 expression in breast cancer: a highly sensitive and specific marker of metaplastic carcinoma // Am J Surg Pathol, 2004; 28:1506-1512
Liu H, Fan Q, Zhang Z, Li X, Yu H, Meng F. Basal-HER2 phenotype shows poorer survival than basal-like phenotype in hormone receptor-negative invasive breast cancers // Hum. Pathol, 2008; 39:167-174
Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma // Mod Pathol, 2006; 19:264-271
Manie, E, Vincent-Salomon A, Lehmann-Che J, Pierron G, Turpin E, Warcoin M, Gruel N, Lebigot I, Sastre-Garau X, Lidereau R, Remenieras A, Feunteun J, Delattre O, de Thé H, Stoppa-Lyonnet D, Stern MH. High frequency of TP53 mutation in BRCA1 and sporadic basal-like carcinomas but not in BRCA1 luminal breast tumors // Cancer Res, 2009; 69:663-671
Nielsen TO, Hsu FD, Jensen K, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma // Clin Cancer Res, 2004; 10:5367-5374
Phipps AI, Malone KE, Porter PL, Daling JR, Li CI. Reproductive and hormonal risk factors for postmenopausal luminal, HER-2-overexpressing, and triple-negative breast cancer // Cancer, 2008; 113:1521-1526
Popovska SL, Ooi A, Ivanov IN, Ivanova NG, Dineva TB. Triple-negative breast cancer does not fully overlap with "basal-like" molecular profile - a morphological and immunohistochemical study // J Biomed Clin Res, 2010; 3:45-50
Raica M, Jung I, Cimpean AM, Suciu C, Muresan AM. From conventional pathologic diagnosis to the molecular classification of breast carcinoma: are we ready for the change? // RJME, 2009; 50:5-13
Rakha EA, El-Sayed ME, Green AR, Paish EC, Lee AHS, Ellis IO. Breast carcinoma with basal differentiation: a proposal for pathology definition based on basal cytokeratin expression // Histopathology, 2007; 50:434-438
Rakha EA, Reis-Filho JS, Ellis IO. Basal-Like Breast Cancer: A Critical Review // J Clin Oncol, 2008; 26:2568-2581
Rastelli F, Biancanelli S, Falzetta A, Martignetti A, Casi C, Bascioni R, Giustini L, Crispino S. Triple-negative breast cancer: current state of the art // Tumori, 2010; 96:875-888
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, Van De Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications // Proc Natl Acad Sci USA, 2001; 98:10869-10874
Spitale A, Mazzola P, Soldini D, Mazzucchelli L, Bordoni A. Breast cancer classification according to immunohistochemical markers: clinicopathologic features and short-term survival analysis in a population-based study from the South of Switzerland // Ann Oncol, 2009; 20: 628-635
Tavassoli FA, Devilee P. Tumours of the breast // In: Tavassoli FA, Devilee P. World Health Organization: Tumours of the Breast and Female Genital Organs. 1st ed. Lyon, IARC Press; 2003; 9-112
Winter J. Morphological and immunophenotypic analysis of basal-like carcinoma of the breast // Bioscience Horizons, 2008; 1:19-27
Zaha DC, Lazar E, Lazureanu C. Clinicopathologic features and five years survival analysis in molecular subtypes of breast cancer // RJME, 2010; 51:85-89