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Association of immunohistochemical p53 tumor suppressor gene protein overexpression with prognosis in highly proliferative human mammary adenocarcinomas

  • Société International de Chirurgie-Manuscripts Presented at the 35th World Congress of the International Society of Surgery, Hong Kong, August 1993
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Abstract

An increasing body of evidence suggests that in addition to conventional histopathologic tumor characteristics, DNA content measurements, cell kinetic data, and investigatios of tumor suppressor gene expressions might be of valuable information in breast cancer patients. Against this background we investigated immunohistochemically overexpression of the interphase associated protein proliferating cell nuclear antigen (PCNA) and the mutant p53 protein in routinely paraffin-embedded surgical specimens from 180 breast cancer patients with known nuclear DNA profiles. The mean clinical follow-up was 16 years (range 13–20 years). The percentage of PCNA immunoreactive tumor cell nuclei ranged between <5% and 60% (mean 13.59±10.85%). There was a direct association between high levels of PCNA expression (>20%) and p53 protein overexpression (p=0.019). Mutant p53 protein overexpression was found in 44 of 180 (24%) cases and was significantly related to high histologic tumor grade (p=0.004), DNA aneuploidy (p=0.001), and high levels of PCNA expression (p=0.001). Patients with highly proliferative carcinomas (>20% PCNA expression) had a shortened distant metastases-free survival when their neoplasms overexpressed p53. In contrast, the distant metastases-free survival of patients with highly proliferative, p53-negative tumors was significantly longer (p=0.03). Immunohistochemical p53 protein overexpression thus appears to be indicative of an increased malignant potential in breast cancer patients. Highly proliferative tumors composed of p53 immunoreactive neoplastic cells clinically seem to behave more aggressively than the highly proliferative p53-negative tumors.

Résumé

En plus des caractéristiques tumorales histopathologiques classiques, y compris le contenu en ADN, la cinétique cellulaire et l'étude de l'expression de gènes suppresseurs sont peut-être importantes dans le bilan d'un cancer du sein. Nous avons examiné par des coupes en paraffine la surexpression immunohistologique de la protéine associée avec l'interphase (le proliferating cell nuclear antigen: PCNA) et la mutante p 53 chez 180 femmes atteintes de cancer de sein ayant des caractéristiques d'ADN connus. Le pourcentage de PCNA immunoréactif variait entre <5 à 60% (moyenne: 13.59±10.85). Il y avait une corrélation positive entre les niveaux d'expression du PCNA (>20%) et la surexpression p 53 (p=0.001), le grade histologique élevé (p=0.009), et l'aneuploïdie d'ADN (p=0.019). La mutante p 53 a été retrouvée chez 44 des 180 (24%) femmes et était significativement associée à un grade tumoral élevé (p= 0.004), à l'aneuploïdie (p=0.001) et à des taux élevés d'expression de PCNA (p=0.001). Les patientes ayant un cancer agressif (>20% d'expression de PCNA) avaient une survie sans métastases plus courte lorsque leur tumeur surexprimait la mutante p53. En revanche, la survie des patientes sans métastase à distance ayant une surexpression de p 53 négative était significativement plus longue (p=0.03). La surexpression p 53 semble correspondre à un potentiel malin élevé chez les femmes ayant un cancer du sein. Les tumeurs hautement prolifératives ayant des cellules à expression p 53 sont cliniquement plus agressives que celles qui ne l'ont pas.

Resumen

Existe evidencia creciente que indica que, además de las características histopatológicas convencionales, incluyendo la determinación de contenido de DNA, los datos de cinética celular y la investigación de la expresión del gen supresor de tumores podrian suministrar información valiosa en pacientes con cáncer mamario. En consecuencia, hemos investigado por métodos inmunohistoquímicos la sobreexpresión de la proteína PCNA (proliferating cell nuclear antigen) asociada con la interfaz y de la proteina mutante p53 en especímenes quirúrgicos fijados rutinariamente en parafina provenientes de 180 pacientes con cáncer mamario con perfiles conocidos de DNA nuclear. El periodo promedio de seguimiento clínico fue 16 años (13–20 años). El porcentaje de núcleos de células tumorales inmunoreactivos a PCNA osciló entre <5% a 60% (valor medio 13.59±10.85). Se encontró una relación directa entre los altos niveles de expresión de PCNA (> 20%) y sobreexpresión de proteína p53 (P=0.001), un alto grado histológico en el tumor (P=0.009) y aneuploidia de DNA (P=0.019). Se encontró sobreexpresión de proteína p53 en 44 de 180 (24%) casos y con relación significativa con el alto grado histológico tumoral (P=0.004), aneuplodia de DNA (P=0.001) y altos niveles de expresión de PCNA (P=0.001). Las pacientes con carcinomas muy proliferativos (expresión de PCNA>20%) exhibieron una más corta sobrevida libre de metástasis a distancia cuando su tumor presentó sobreexpresión de p53. En contraste, la sobrevida libre de metástasis distantes en pacientes con tumores altamente proliferativos y p53 negativos apareció significativamente prolongada (P=0.03). Por consiguiente, la sobreexpresión de proteína p53 parece ser un indicador de un incrementado potencial de malignidad en pacientes con cáncer mamario. Los tumores altamente proliferativos, compuestos de céluls neoclásicas inmunoreactivas a p53 parecen tener un comportamiento clínico más agresivo en comparación con los tumores altamente proliferativos pero p53 negativos.

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Authors and Affiliations

  1. Department of General Surgery, Johann-Wolfgang Goethe University Hospital, D-60590, Frankfurt, Germany

    Hendrik Schimmelpenning M.D., Ph.D.

  2. Department of Tumor Pathology, Karolinska Hospital and Institute, S-17176, Stockholm, Sweden

    Elina T. Eriksson M.D., Ph.D., Anders Zetterberg M.D., Ph.D. & Gert U. Auer M.D., Ph.D.

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  1. Hendrik Schimmelpenning M.D., Ph.D.
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  2. Elina T. Eriksson M.D., Ph.D.
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  3. Anders Zetterberg M.D., Ph.D.
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  4. Gert U. Auer M.D., Ph.D.
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Schimmelpenning, H., Eriksson, E.T., Zetterberg, A. et al. Association of immunohistochemical p53 tumor suppressor gene protein overexpression with prognosis in highly proliferative human mammary adenocarcinomas. World J. Surg. 18, 827–832 (1994). https://doi.org/10.1007/BF00299077

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