Background: Cell proliferative activity (PA) is one of the most important biological mechanisms in oncogenesis and has high prognostic significance in several types of neoplasms. A Medline based search up to May 2004 selected 6,743 reports containing the terms “proliferative activity and tumor”. However, what was measured in most tumor studies, is not the “actual” PA, since the mechanisms responsible for PA are the proportion of cells committed to cycle (growth fraction, or G) and the speed of the cycle, which is inversely proportional to the generation time (T) [van Diest PJ et al J Clin Pathol 1998; 51: 716-724]. PA can be mathematically represented by the equation PA=G/T [van Diest et al. 1998]. It is clear from this equation that neither G, nor T can by itself define the actual PA of a tumor [Brugal G. Virchows Arch 1995; 427: 323-341]. On routinely processed tissues, the tumor growth fraction can be easily assessed by Ki67/MIB1 labelling index, and the speed of cell cycle by the quantity of AgNOR proteins, which reflects the rapidity of cell proliferation [Derenzini et al. Lab Invest 1995; 73: 497-502]. Therefore, the “actual” proliferative activity of a tumor can be simply expressed by the equation [PA=Ki67/MIB1 scores x AgNOR quantity]. We applied this formula to verify the value of cell proliferation in patients with male breast carcinoma (MBC). Materials and Methods: Fifty previously untreated patients (mean age: 62.2 years) with invasive ductal carcinoma were retrospectively studied. Nine were grade 1, 29 grade 2 and 12 grade 3 carcinoma; 15 were pT1, 17 pT2 and 18 pT4; 14 were node negative and 21 node positive. All patients underwent surgery, 35 also received adjuvant post-operative therapy. A minimum follow-up of 3 years or to death was available for all cases. On serial sections from formalin-fixed, paraffin embedded specimens, AgNOR area was assessed according to the standardised method, and MIB1 scores were evaluated after immunohistochemistry. Sections were also immunostained for sex steroid hormone receptors, p53, bcl-2, c-erbB-2 and c-myc proteins. Morphometry was performed with an automated image analyser and DNA content was assessed by flow cytometry. Results: The mean PA for the whole series was 95.5 (median: 77, SD: 62, range: 21.4-282). It was greater in G3 (140.3) than in G2 (89.8) or G1 tumors (54.2, p = 0.003); in T2-4 (106.8) than T1 cases (69.3; p = 0.02); in androgen receptors negative (111.2) than positive cases (67.7; p = 0.003), in p53 positive (123.5) than negative cases (62.7; p = 0.0002), in c-myc positive (102.7) than negative cases (62.7; p = 0.003), in cases with large (125.5) than in cases with small nuclear area (65.6; p = 0.0004), and in aneuploid (106.9) than diploid cases (63.7; p =0.02). In univariate analysis, the median survival was 96 months for patients with PA < 77 but only 27 months for those with PA > 77 (p<0.0001). Age, histologic grade, T stage, nuclear area, p53, c-myc and c-erbB-2 expression had also prognostic value. In multivariate analysis, only PA (X2=13.09; p<0.001), c-myc expression (X2=7.12; p=0.008) and T stage (X2=4.43; p=0.03) retained independent prognostic value. Conclusions: Our results indicate that PA is associated with factors reflecting the biologic aggressiveness of MBC and that the “actual” proliferative activity, as expressed by the product [AgNOR area x MIB-1 score], is the most significant prognostic factor in MBC.
Cell proliferative activity in male breast carcinoma
PICH, Achille;
2004-01-01
Abstract
Background: Cell proliferative activity (PA) is one of the most important biological mechanisms in oncogenesis and has high prognostic significance in several types of neoplasms. A Medline based search up to May 2004 selected 6,743 reports containing the terms “proliferative activity and tumor”. However, what was measured in most tumor studies, is not the “actual” PA, since the mechanisms responsible for PA are the proportion of cells committed to cycle (growth fraction, or G) and the speed of the cycle, which is inversely proportional to the generation time (T) [van Diest PJ et al J Clin Pathol 1998; 51: 716-724]. PA can be mathematically represented by the equation PA=G/T [van Diest et al. 1998]. It is clear from this equation that neither G, nor T can by itself define the actual PA of a tumor [Brugal G. Virchows Arch 1995; 427: 323-341]. On routinely processed tissues, the tumor growth fraction can be easily assessed by Ki67/MIB1 labelling index, and the speed of cell cycle by the quantity of AgNOR proteins, which reflects the rapidity of cell proliferation [Derenzini et al. Lab Invest 1995; 73: 497-502]. Therefore, the “actual” proliferative activity of a tumor can be simply expressed by the equation [PA=Ki67/MIB1 scores x AgNOR quantity]. We applied this formula to verify the value of cell proliferation in patients with male breast carcinoma (MBC). Materials and Methods: Fifty previously untreated patients (mean age: 62.2 years) with invasive ductal carcinoma were retrospectively studied. Nine were grade 1, 29 grade 2 and 12 grade 3 carcinoma; 15 were pT1, 17 pT2 and 18 pT4; 14 were node negative and 21 node positive. All patients underwent surgery, 35 also received adjuvant post-operative therapy. A minimum follow-up of 3 years or to death was available for all cases. On serial sections from formalin-fixed, paraffin embedded specimens, AgNOR area was assessed according to the standardised method, and MIB1 scores were evaluated after immunohistochemistry. Sections were also immunostained for sex steroid hormone receptors, p53, bcl-2, c-erbB-2 and c-myc proteins. Morphometry was performed with an automated image analyser and DNA content was assessed by flow cytometry. Results: The mean PA for the whole series was 95.5 (median: 77, SD: 62, range: 21.4-282). It was greater in G3 (140.3) than in G2 (89.8) or G1 tumors (54.2, p = 0.003); in T2-4 (106.8) than T1 cases (69.3; p = 0.02); in androgen receptors negative (111.2) than positive cases (67.7; p = 0.003), in p53 positive (123.5) than negative cases (62.7; p = 0.0002), in c-myc positive (102.7) than negative cases (62.7; p = 0.003), in cases with large (125.5) than in cases with small nuclear area (65.6; p = 0.0004), and in aneuploid (106.9) than diploid cases (63.7; p =0.02). In univariate analysis, the median survival was 96 months for patients with PA < 77 but only 27 months for those with PA > 77 (p<0.0001). Age, histologic grade, T stage, nuclear area, p53, c-myc and c-erbB-2 expression had also prognostic value. In multivariate analysis, only PA (X2=13.09; p<0.001), c-myc expression (X2=7.12; p=0.008) and T stage (X2=4.43; p=0.03) retained independent prognostic value. Conclusions: Our results indicate that PA is associated with factors reflecting the biologic aggressiveness of MBC and that the “actual” proliferative activity, as expressed by the product [AgNOR area x MIB-1 score], is the most significant prognostic factor in MBC.
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