Virchows Archiv

, Volume 450, Issue 6, pp 627–636 | Cite as

Grading invasive ductal carcinoma of the breast: advantages of using automated proliferation index instead of mitotic count

  • Ossama Tawfik
  • Bruce F. Kimler
  • Marilyn Davis
  • Christopher Stasik
  • Sue-Min Lai
  • Matthew S. Mayo
  • Fang Fan
  • John K. Donahue
  • Ivan Damjanov
  • Patricia Thomas
  • Carol Connor
  • William R. Jewell
  • Holly Smith
  • Carol J. Fabian
Original Article


Breast carcinomas are graded according to the “Nottingham modification of the Bloom–Richardson system” (SBR). The system is hindered, however, by lack of precision in assessing all three parameters including nuclear grade, mitosis, and tubular formation, leading to an element of subjectivity. Our objective was to evaluate a new grading system [the nuclear grade plus proliferation (N+P) system] for subjectivity, ease, and better representation of tumor biology. Its components are nuclear grade and automated proliferation index. Invasive ductal carcinomas, consisting of 137 SBR grade I, 247 grade II, and 266 grade III, were re-evaluated by the N+P system. The two systems were compared with each other and correlated with patients’ overall survival, tumor size, angiolymphatic invasion, lymph node status, and biomarker status including estrogen receptor, progesterone receptor, p53, epidermal growth factor receptor, BCL-2, and Her-2. Although there was an agreement between the two systems with histologic and prognostic parameters studied, there was 37% disagreement when grading individual tumors. Fifty-three percent of SBR grade II tumors were “down-graded” to N+P grade I, and 7% were “up-graded” to N+P grade III. Distinction among the different histologic grades for overall survival curves was better indicated by the N+P than the SBR system.


Invasive breast carcinoma grading MIB-1 (Ki-67) Immunohistochemistry Automation Image analysis Survival 


  1. 1.
    Bane AL, Tjan S, Parkes RK, Andrulis I, O’Malley FP (2005) Invasive lobular carcinoma: to grade or not to grade. Mod Pathol 18:621–628PubMedCrossRefGoogle Scholar
  2. 2.
    Black MM, Barclay THC, Hankey BF (1975) Prognosis in breast cancer utilizing histologic characteristics of the primary tumor. Cancer 36:2048–2055PubMedCrossRefGoogle Scholar
  3. 3.
    Bloom HJG, Richardson WW (1957) Histologic grading in breast cancer: a study of 1,409 cases of which 359 have been followed for 15 years. Br J Cancer 11:359–377PubMedGoogle Scholar
  4. 4.
    Boiesen P, Bendahl PO, Anagnostaki L, Domanski H, Holm E, Idvall I, Johansson S, Ljungberg O, Ringberg A, Ostberg G, Ferno M (2000) Histologic grading in breast cancer—reproducibility between seven pathologic departments. South Sweden Breast Cancer Group. Acta Oncol 39:41–45PubMedCrossRefGoogle Scholar
  5. 5.
    Brown RW, Allred CD, Clark GM, Osborne CK, Hilsenbeck SG (1996) Prognostic value of Ki-67 compared to S-phase fraction in axillary node-negative breast cancer. Clin Cancer Res 2:585–592PubMedGoogle Scholar
  6. 6.
    Cady B, Stone MD, Schuler JG, Thakur R, Wanner MA, Lavin PT (1996) The new era in breast cancer. Invasion, size and nodal involvement dramatically decreasing as a result of mammography screening. Arch Surg 131:301–308PubMedGoogle Scholar
  7. 7.
    Cattoretti G, Becker MH, Key G, Duchrow M, Schluter C, Galle J, Gerdes J (1992) Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB-1 and MIB-3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol 168:357–363PubMedCrossRefGoogle Scholar
  8. 8.
    Chia SK, Speers CH, Bryce CJ, Hayes MM, Olivotto IA (2004) Ten-year outcomes in a population-based cohort of node-negative, lymphatic, and vascular invasion-negative early breast cancers without adjuvant systemic therapies. J Clin Oncol 22:1630–1637PubMedCrossRefGoogle Scholar
  9. 9.
    Clahsen PC, van de Velde CJ, Duval C, Pallud C, Mandard AM, Delobelle-Deroide A, van den Broek L, van de Vijver MJ (1999) The utility of mitotic index, oestrogen receptor and Ki-67 measurements in the creation of novel prognostic indices for node-negative breast cancer. Eur J Surg Oncol 25:356–363PubMedCrossRefGoogle Scholar
  10. 10.
    Dalton LW, Page DL, Dupont WD (1994) Histologic grading of breast carcinoma. A reproducibility study. Cancer 73:2765–2770PubMedCrossRefGoogle Scholar
  11. 11.
    Dalton LW, Pinder SE, Elston CE, Page DL, Dupont WD, Blamey RW (2000) Histologic grading of breast cancer: linkage of patient outcome with level of pathologist agreement. Mod Pathol 13:730–735PubMedCrossRefGoogle Scholar
  12. 12.
    Davis BW, Gelber R, Goldhirsch A, Hartmann WH, Hollaway L, Russell I, Rudenstam CM (1985) Prognostic significance of peritumoral vessel invasion in clinical trials of adjuvant therapy for breast cancer with axillary lymph node metastasis. Human Pathol 16:1212–1218CrossRefGoogle Scholar
  13. 13.
    Delides GS, Garas G, Georgouli G, Jiortziotis D, Lecca J, Liva T, Elemenoglou J (1982) Intralaboratory variations in the grading of breast carcinoma. Arch Pathol Lab Med 106:126–128PubMedGoogle Scholar
  14. 14.
    Eisen T, Smith IE, Johnston S, Ellis PA, Prendiville J, Seymour MT, Walsh G, Ashley S (1998) Randomized phase II trial of infusional fluorouracil, epirubicin and cyclophosphamide versus infusional fluorouracil, epirubicin and cisplatin in patients with advanced breast cancer. J Clin Oncol 16:1350–1357PubMedGoogle Scholar
  15. 15.
    Ellis IO, Galea M, Broughton N, Locker A, Blamey RW, Elston CW (1992) Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow up. Histopathology 20:479–489PubMedCrossRefGoogle Scholar
  16. 16.
    Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow up. Histopathology 19:403–410PubMedCrossRefGoogle Scholar
  17. 17.
    Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr, Hoehn JL, Lees AW, Dimitrov NV, Bear HD (1998) Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672–2685PubMedGoogle Scholar
  18. 18.
    Fisher ER, Redmond C, Fisher B (1980) Histologic grading of breast cancer. Pathol Annu 15:239–251PubMedGoogle Scholar
  19. 19.
    Frierson HF Jr, Wolber RA, Berean KW, Franquemont DW, Gaffey MJ, Boyd JC, Wilbur DC (1995) Interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for infiltrating ductal carcinoma. Am J Clin Pathol 103:195–198PubMedGoogle Scholar
  20. 20.
    Gerdes J, Lemke H, Baisch H, Wacker H-H, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133:1710–1715PubMedGoogle Scholar
  21. 21.
    Greenhough RB (1925) Varying degree of malignancy in cancer of the breast. J Cancer Res 9:453–463Google Scholar
  22. 22.
    Haagensen CD (1933) The basis for histologic grading of the breast. Am J Cancer 1:285–327Google Scholar
  23. 23.
    Haerslev T, Jacobsen GK, Zedeler K (1996) Correlation of growth fraction by Ki-67 and proliferating cell nuclear antigen (PCNA) immunohistochemistry with histopathological parameters and prognosis in primary breast carcinomas. Breast Cancer Res Treat 37:101-113PubMedCrossRefGoogle Scholar
  24. 24.
    Harvey JM, de Klerk NH, Sterrett GF (1992) Histological grading in breast cancer. Interobserver agreement and relation to other prognostic factors including ploidy. Pathology 24:63–68PubMedGoogle Scholar
  25. 25.
    Hilbe W, Gachter A, Duba HC, Dirnhofer S, Eisterer W, Schmid T, Mildner A, Bodner J, Woll E (2003) Comparison of automated cellular imaging system and manual microscopy for immunohistochemically stained cryostat sections of lung cancer specimens applying p53, Ki-67 and p120. Oncol Rep 10:15–20PubMedGoogle Scholar
  26. 26.
    Hlupic L, Jakic-Razumovic J, Bozikov J, Coric M, Belev B, Vrbanec D (2004) Prognostic values of different factors in breast carcinoma. Tumori 90:112–119PubMedGoogle Scholar
  27. 27.
    Jansen RL, Hupperets PS, Arends JW, Joosten-Achjanie SR, Volovics A, Schouten HC, Hillen HF (1998) MIB-1 labeling index is an independent prognostic marker in primary breast cancer. Br J Cancer 78:460–465PubMedGoogle Scholar
  28. 28.
    Keshgegian AA, Cnaan A (1995) Proliferation markers in breast carcinoma. Mitotic figure count, S-phase fraction, proliferating cell nuclear antigen, Ki-67 and MIB-1. Am J Clin Pathol 104:42–49PubMedGoogle Scholar
  29. 29.
    Kronqvist P, Montironi R, Kuopio T, Collan YU (1997) Subjective breast cancer grading. Analyses of reproducibility after application of Bayesian belief networks. Anal Quant Cytol Histol 19:423–429PubMedGoogle Scholar
  30. 30.
    Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, Farid LM, Venter D, Antoniou A, Storfer-Isser A, Smyth E, Steel CM, Haites N, Scott RJ, Goldgar D, Neuhausen S, Daly PA, Ormiston W, McManus R, Scherneck S, Ponder BA, Ford D, Peto J, Stoppa-Lyonnet D, Bignon YJ, Struewing JP, Spurr NK, Bishop DT, Klijn JG, Devilee P, Cornelisse CJ, Lasset C, Lenoir G, Barkardottir RB, Egilsson V, Hamann U, Chang-Claude J, Sobol H, Weber B, Stratton MR, Easton DF (1998) Multifactorial analysis of differences between sporadic breast cancer and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90:1138–1145PubMedCrossRefGoogle Scholar
  31. 31.
    Le Doussal V, Tubiana-Hulin M, Friedman S, Hacene K, Spyratos F, Brunet M (1989) Prognostic value of histologic grade nuclear components of Scarff–Bloom–Richardson (SBR). An improved score modification based on a multivariate analysis of 1262 invasive ductal breast carcinomas. Cancer 64:1914–1921PubMedCrossRefGoogle Scholar
  32. 32.
    Lehr HA, Hansen DA, Kussick S, Li M, Hwang H, Krummenauer F, Trouet S, Gown AM (1999) Assessment of proliferative activity in breast cancer: MIB-1 immunohistochemistry versus mitotic figure count. Human Pathol 30:1314–1320CrossRefGoogle Scholar
  33. 33.
    Leonardi E, Girlando S, Serio G, Mauri FA, Perrone G, Scampini S, Dalla Palma P, Barbareschi M (1992) PCNA and Ki67 expression in breast carcinoma: correlations with clinical and biological variables. J Clin Pathol 45:416–419PubMedCrossRefGoogle Scholar
  34. 34.
    Marchetti E, Querzoli P, Marzola A, Bagni A, Ferretti S, Fabris G, Nenci I (1990) Assessment of proliferative rate of breast cancer by Ki-67 monoclonal antibody. Mod Pathol 3:31–35PubMedGoogle Scholar
  35. 35.
    Mengel M, von Wasielewski R, Wiese B, Rudiger T, Muller-Hermelink HK, Kreipe H (2002) Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labeling index in large multi-centre trial. J Pathol 198:292–299PubMedCrossRefGoogle Scholar
  36. 36.
    Meyer JS, Alvarez C, Milikowski C, Olson N, Russo I, Russo J, Glass A, Zehnbauer BA, Lister K, Parwaresch R, Cooperative Breast Cancer Tissue Resource (2005) Breast carcinoma malignancy grading by Bloom–Richardson system vs. proliferation index: reproducibility of grade and advantages of proliferation index. Mod Pathol 18:1067–1078PubMedCrossRefGoogle Scholar
  37. 37.
    Offersen BV, Sorensen FB, Knoop A, Overgaard J, Danish Breast Cancer Cooperative Tumour Biology Committee (2003) The prognostic relevance of estimates of proliferative activity in early breast cancer. Histopathology 43:573–582PubMedCrossRefGoogle Scholar
  38. 38.
    Page DL, Ellis IO, Elston CW (1995) Histologic grading of breast cancer. Let’s do it. Am J Clin Pathol 103:123–124PubMedGoogle Scholar
  39. 39.
    Patey DH, Scarff RW (1928) The position of histology in the prognosis of the breast. Lancet 1:801–804CrossRefGoogle Scholar
  40. 40.
    Petit T, Wilt M, Velten M, Millon R, Rodier JF, Borel C, Mors R, Haegele P, Eber M, Ghnassia JP (2004) Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients with neoadjuvant anthracycline based chemotherapy. Eur J Cancer 40:205–211PubMedCrossRefGoogle Scholar
  41. 41.
    Pinder SE, Murray S, Ellis IO, Trihia H, Elston CW, Gelber RD, Goldhirsch A, Lindtner J, Cortes-Funes H, Simoncini E, Byrne MJ, Golouh R, Rudenstam CM, Castiglione-Gertsch M, Gusterson BA (1998) The importance of histologic grade in invasive breast carcinoma and response to chemotherapy. Cancer 83:1529–1539PubMedCrossRefGoogle Scholar
  42. 42.
    Pinder SE, Wencyk P, Sibbering DM, Bell JA, Elston CW, Nicholson R, Robertson JF, Blamey RW, Ellis IO (1995) Assessment of the new proliferation marker MIB-1 in breast carcinoma using image analysis: associations with other prognostic factors and survival. Br J Cancer 71:146–149PubMedGoogle Scholar
  43. 43.
    Powles TJ, Hickish TF, Makris A, Ashley SE, O’Brien ME, Tidy VA, Casey S, Nash AG, Sacks N, Cosgrove D et al (1995) Randomized trial of chemoendocrine therapy started before and after surgery for treatment of primary breast cancer. J Clin Oncol 13:547–552PubMedGoogle Scholar
  44. 44.
    Raabe NK, Schistad O, Sauer T, Bofin A, Kaaresen R, Fossaa SD (1997) Prognosis of radically operated breast carcinoma patients. A retrospective study of 167 consecutive patients with emphasis on histopathological grading, reproducibility and mean nuclear area. Acta Pathol Microbiol Immunol Scand APMIS 105:363–370Google Scholar
  45. 45.
    Robbins P, Pinder S, de Klerk N, Dawkins H, Harvey J, Sterrett G, Ellis I, Elston C (1995) Histological grading of breast carcinomas: a study of interobserver agreement. Human Pathol 26:873–879CrossRefGoogle Scholar
  46. 46.
    Rudolph P, MacGrogan G, Bonichon F, Frahm SO, de Mascarel I, Trojani M, Durand M, Avril A, Coindre JM, Parwaresch R (1999) Prognostic significance of Ki-67 and topoisomerase II alpha expression in infiltrating ductal carcinoma of the breast. Breast Cancer Res Treat 55:61–71PubMedCrossRefGoogle Scholar
  47. 47.
    Sediman JD, Schnaper LA, Aisner SC (1995) Relationship of the size of the invasive component of the primary breast carcinoma to axillary lymph node metastasis. Cancer 75:65–71CrossRefGoogle Scholar
  48. 48.
    Sikka M, Agarwal S, Bhatia A (1999) Interobserver agreement of the Nottingham histologic grading scheme for infiltrating duct carcinoma breast. Indian J Cancer 36:149–153PubMedGoogle Scholar
  49. 49.
    Sinha PS, Bendall S, Bates T (2000) Does routine grading of invasive lobular cancer of the breast have the same prognostic significance as for ductal cancers? Eur J Surg Oncol 26:733–737PubMedCrossRefGoogle Scholar
  50. 50.
    Spyratos F, Ferrero-Pous M, Trassard M, Hacene K, Phillips E, Tubiana-Hulin M, Le Doussal V (2002) Correlation between MIB-1 and other proliferation markers: clinical implications of the MIB-1 cutoff value. Cancer 94:2151–2159PubMedCrossRefGoogle Scholar
  51. 51.
    Stenkvist B, Bengtsson E, Eriksson O, Jarkrans T, Nordin B, Westman-Naeser S (1982) Histopathological systems of breast classification: reproducibility and clinical significance. J Clin Pathol 36:392–398CrossRefGoogle Scholar
  52. 52.
    Tavassoli FA, Devilee P (eds) (2003) World Health Organization classification of tumours. Pathology and genetics. Tumours of the breast and female genital organs. Chapter 1. IARC, Lyon, France, pp 9–112Google Scholar
  53. 53.
    Tawfik O, Davis MK, Clark J, Fan F, Damjanov I, Namiq A, Thomas P, Kimler BF (2006) A newly proposed semi-automated method of grading ductal carcinoma in situ of the breast. 19 (Suppl):43A (abstract 187)Google Scholar
  54. 54.
    Theissig F, Kunze KD, Haroske G, Meyer W (1990) Histological grading of breast cancer. Interobserver, reproducibility and prognostic significance. Pathol Res Pract 186:732–736PubMedGoogle Scholar
  55. 55.
    Tot T (2006) The limited prognostic value of measuring and grading small invasive breast carcinomas: the whole sick lobe versus the details within it. Med Sci Monit 12:RA170–RA175PubMedGoogle Scholar
  56. 56.
    Trihia H, Murray S, Price K, Gelber RD, Golouh R, Goldhirsch A, Coates AS, Collins J, Castiglione-Gertsch M, Gusterson BA, International Breast Cancer Study Group (2003) Ki-67 expression in breast carcinoma. Its association with grading systems, clinical parameters, and other prognostic factors—a surrogate marker? Cancer 97:1321–1331PubMedCrossRefGoogle Scholar
  57. 57.
    Von Hansemann D (1892) Ueber die Anaplasie der Geschwulstzellen und die asymmetrische mitose. Virchows Arch Pathol Anat 129:436–449CrossRefGoogle Scholar
  58. 58.
    Warnberg F, Nordgren H, Bergkvist L, Holmberg L (2001) Tumour markers in breast carcinoma correlate with grade rather than with invasiveness. Br J Cancer 85:869–874PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Ossama Tawfik
    • 1
  • Bruce F. Kimler
    • 2
  • Marilyn Davis
    • 1
  • Christopher Stasik
    • 1
  • Sue-Min Lai
    • 3
  • Matthew S. Mayo
    • 3
    • 5
  • Fang Fan
    • 1
  • John K. Donahue
    • 1
  • Ivan Damjanov
    • 1
  • Patricia Thomas
    • 1
  • Carol Connor
    • 4
  • William R. Jewell
    • 4
  • Holly Smith
    • 5
  • Carol J. Fabian
    • 6
  1. 1.Department of Pathology and Laboratory MedicineKansas University Medical CenterKansas CityUSA
  2. 2.Department of Radiation OncologyKansas University Medical CenterKansas CityUSA
  3. 3.Department of Preventive Medicine and Public HealthKansas University Medical CenterKansas CityUSA
  4. 4.Department of SurgeryKansas University Medical CenterKansas CityUSA
  5. 5.Center for Biostatistics and Advanced InformaticsKansas University Medical CenterKansas CityUSA
  6. 6.Department of Medicine, Oncology DivisionKansas University Medical CenterKansas CityUSA

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