Ductal carcinoma in situ lesions of the breast: correlation between histopathologic features and p53, HER2/neu, bcl-2 and PCNA expression

Abstract

Objective: The histopathological subtype, nuclear grade and comedonecrosis are important features for ductal
carcinoma in situ (DCIS) of the breast. The aim of this study was to determine correlation between histopathologic
properties of DCIS and p53, HER2/neu, bcl-2 and PCNA overexpression.
Method: We evaluated 40 cases of DCIS for p53, HER2/neu, bcl-2 and PCNA overexpression by using
immunohistochemical methods. We divided lesions into two groups. Low/intermediate grade DCIS cases were
included in group 1 (low grade DCIS) and high grade DCIS were included in group 2 (high grade DCIS). Histologic
paterns were also evaluated. Comedo type and non-comedo type DCIS groups were formed.
Results: A total of 40 DCIS including 12 high grade, 28 low grade, 8 comedo type and 32 non-comedo type were
revealed. P53 and HER2/neu overexpressions were seen 37,5%, 62,5% in comedo type DCIS and 6,5%, 3,1% in noncomedo type DCIS, respectively. P53 and HER2/neu overexpressions were not seen in low grade DCIS and were seen
41,7% and 50% in high grade DCIS, respectively. Strong cytoplasmic staining with bcl-2 was not seen in high grade
DCIS and was seen 60% in low grade DCIS. There was significant difference statistically between groups for all of
these overexpressions (p<0,05).
Conclusions: P53 and HER/neu overexpressions were associated with poor prognostic factors such as comedo type
and high grade. Strong cytoplasmic bcl-2 staining was associated with good prognostic factors such as non-comedo
type and low grade. These results contribute to define DCIS subtypes that have different biological behaviour.

Keywords

• Ductal carcinoma in situ
• breast cancer
• p53
• HER2/neu
• bcl-2

Memenin Duktal Karsinoma in Situ Lezyonları: Histopatolojik özellikler ile p53, HER2/neu, bcl-2 ve PCNA Ekspresyonu arasındaki ilişki

Abstract

Amaç: Histopatolojik alt tip, nükleer derece ve komedonekroz memenin duktal karsinoma in situ (DKIS) lezyonları için önemli özelliklerdir. Bu çalışmanın amacı DKIS’nin histopatolojik özellikleri ile p53, HER2/neu, bcl-2 ve PCNA overekspresyonu arasındaki ilişkinin belirlenmesidir. 

Yöntemler: DKIS tanısı almış 40 olgu immünohistokimyasal metodlar kullanılarak p53, HER2/neu, bcl-2 ve PCNA overekspresyonu açısından değerlendirildi. Düşük/ intermediate dereceli lezyonlar grup 1’e (düşük dereceli DKIS), yüksek dereceli olgular grup 2’ye (yüksek dereceli DKIS) dahil edildi. Ayrıca histolojik paternler değerlendirildi. Komedo tip ve non-komedo tip DKIS grupları oluşturuldu. 

Bulgular: Toplam 40 olgunun 12’si yüksek dereceli, 28’i düşük dereceli, 8’i komedo tip ve 32’si non-komedo tip DKIS olarak belirlendi. Komedo tip DKIS olgularında sırasıyla %37,5, %62,5’inde p53 ve HER2/neu overekspresyonu izlenirken, non-komedo tip DKIS olgularında bu oran % 6,5, %3,1 idi. Yüksek dereceli olgularda sırasıyla %41,7, %50’sinde p53 ve HER2/neu overekspresyonu izlenirken, düşük dereceli olguların hiçbirinde p53 ve HER2/neu overekspresyonu gözlenmedi. Bcl-2 ile kuvvetli sitoplazmik boyanma yüksek dereceli olguların hiçbirinde izlenmezken, düşük dereceli olguların %60’ında izlendi. Tüm bu overekspresyonlar için gruplar arasında istatistiksel olarak anlamlı fark vardı (p<0,05). 

Sonuçlar: P53 ve HER2/neu overekspresyonu komedo tip ve yüksek derece gibi kötü prognostik faktörlerle ilişkili bulundu. Bcl-2 ile kuvvetli sitoplazmik boyanma non-komedo tip ve düşük derece gibi iyi prognostik faktörlerle ilişkili bulundu. Bu sonuçlar farklı biyolojik davranışa sahip DKIS alt tiplerinin tanımlanmasına katkı sağlayacaktır. 

Keywords

• Duktal karsinoma in situ
• meme kanseri
• p53
• HER2/neu

References

1. 1. Perez AA, Balabram D, Salles MA, Gobbi H. Ductal carcinoma in situ of the breast: correlation between histopathological features and age of the patients. Diagn Pathol. 2014; 9: 227-32.
2. 2. Shan M, Zhang X, Liu X, et al. P16 and p53 play Distinct roles in different subtypes of breast cancer. PLoS One 2013; 8: e76408.
3. 3. Terry G, Ho L, Londesborough P, Duggan C, Hanby A, Cuzick J. The expression of FHIT, PCNA and EGFR in benign and malignant breast lesions. Br J Cancer 2007 Jan 15; 96: 110-7.
4. 4. Tunon G, Ricote M, Ruiz A, et al. Cell cycle control related proteins (p53, p21, and Rb) and transforming growth factor B (TGFB) in benign and carcinomatous (in situ and infilrating) human breast: implications in malignant transformations. Cancer Invest 2006; 24: 119-25.
5. 5. Mylonas I, Makovitzky J, Jeschke U, Briese V, Friese K, Gerber B. Expression of Her2/neu, steroid receptors (ER and PR), Ki67 and p53 in invasive mammary ductal carcinoma associated with ductal carcinoma in situ (DCIS) versus invasive breast cancer alone. Anticancer Research 2005; 25: 1719-24.
6. 6. Davidoff AM, Kernes BJ, Iglehard JD, Marks JR. Maintenance of p53 alterations throughout breast cancer progression. Cancer Res 1991; 51: 2605-10.
7. 7. Yamashita H, Nishio M, Toyama T, et al. Coexistence of HER2 over-expression and p53 protein accumulation is a strong prognostic molecular merker in breast cancer. Breast Cancer Res 2004; 6: R24-R30.
8. 8. Xu R, Perle MA, Inghirami G, et al. Amplification of HER-2/neu gene in HER-2/neu-overexpressing and – nonexpressing breast carcinomas and their synchronous benign, premalignant, and metastatic lesions detected by FISH in archival material. Mod Pathol 2002; 15: 116-24.

9. 9. Tsuda H, Hirohashi S. Multiple developmental pathways of highly aggressive breast cancer disclosed by comparison of histological grade and c-erbB-2 expression patterns in both the noninvasive and invasive portions. Pathol Int 1998; 48: 518-25.
10. 10. Hung MC, Lau YK. Basic science of HER-2/neu: a review. Semin Oncol 1999; 26: 51-9.
11. 11. Hockenbery DM, Zutter M, Hickey W, Nahm M, Korsmeyer SJ. Bcl-2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci U S A 1991; 88: 6961-5.
12. 12. Stewart BW. Mechanisms of apoptosis: integration of genetic, biochemical, and cellular indicators. J Natl Cancer Inst 1994; 86: 1286-96.
13. 13. Leek RD, Kaklamanis L, Pezzella F, Gatter KC, Harris AL. Bcl-2 in normal human breast and carcinoma, association with oestrogen receptor-positive, epidermal growth factor receptor-negative tumours and in situ cancer. Br J Cancer 1994; 69: 135-9.
14. 14. Doglioni C, Dei Tos AP, Laurino L, et al. Bcl-2 expression in breast carcinoma. Mod Pathol 1994; 7: 15A.
15. 15. Mercier I, Gonzales DM, Quann K, et al. CAPER, a novel regulator of human breast cancer progression. Cell Cycle 2014 Apr 15; 13: 1256-64.
16. 16. Mao Y, Wu J, Wang N, et al. A comparative study: immunohistochemical detection of cytosolic thymidine kinase and proliferating cell nuclear antigen in breast cancer. Cancer Invest 2002; 20: 922-31. 17. Agarwal S, Jain R, Rusia U, Gupta RL. Proliferating cell nuclear antigen immunostaining in breast carcinoma and its relationship to clinical and pathological variables. Indian J Pathol Microbiol 1997; 40: 11-16.
17. 18. Mack L, Kerkvliet N, Doig G, O’Malley FP. Relationship of a new histological categorization of the ductal carcinoma in situ of the breast with size and the immunohistochemical expression of p53, c-erbB-2, bcl2, and Ki-67. Hum Pathol 1997; 28: 974-9.
18. 19. Holmes P, Lloyd J, Chervoneva, et al. Prognostic markers and long-term outcomes in ductaı carcinoma in situ of the breast treated with excision alone. Cancer 2011 Aug 15; 117: 3650-7.
19. 20. Chaisson K, Rivere A, Corsetti R, Weiss T, Fuhrman GM. A potential additional variables to consider in the surgical treatment of ductal carcinoma in situ. Ochsner J 2017 Winter;17: 341-4.
20. 21. Ioachim EE, Malamau-Mitsi V, Kamina SA, Goussia AC, Agnantis NJ. Immunohistochemical expression of the bcl-2 protein in breast lesions: correlation with Bax, p53, Rb, c-erbB-2, EGFR and proliferation indices. Anticancer Res 2000; 20: 4221-6.
21. 22. Larsen MS, Bjerre K, Giobbie-Hurder A, et al. Prognostic value of Bcl-2 in two independent populations of estrogen receptor positive breast cancer patients treated with adjuvant endocrine therapy. Acta Oncol. 2012 Jul; 51:781-9.