Prognostic significance of the alterations of the G1-S checkpoint in localized leiomyosarcoma of the peripheral soft tissue.
BACKGROUND
The aim of this study was to investigate the expression of cell cycle regulators p53, p16, cyclin-D1, and retinoblastoma (Rb) gene protein in leiomyosarcoma of the peripheral soft in order to identify expression profiles potentially useful for clinical prognostic purposes.


METHODS
A tissue microarray representing 70 localized leiomyosarcomas of the limbs and limb girdles was created with 3 representative cores from each tumor. Immunohistochemical staining was performed for p53, p16, cyclin-D1, and Rb using standard techniques. Staining was scored as either absent-low (<20% of neoplastic cells) or moderate-diffuse (≥20%). Outcome analysis was performed for local recurrence-free survival (LFS), metastatic disease-free survival (MDFS), and disease-specific survival (DSS).


RESULTS
Kaplan-Meier analysis of survival revealed that no single alteration of the factors examined was associated with outcome, but tumors showing concomitant alteration of p16 and p53 were characterized by reduced MDFS and DSS (P = 0.01 and P < 0.001, respectively). In addition, patients who received adjuvant therapy consisting of radiotherapy alone or radiotherapy and chemotherapy had a better DSS than those receiving surgery alone or surgery and chemotherapy (P = 0.05). In multivariate analysis, altered p16/p53 remained the only parameter predictive of MDFS and DSS (P = 0.048, hazard ratio [HR] = 2.488, 95% confidence interval [95% CI] 1.006-5.116; P = 0.043, HR = 2.498, 95% CI 1.029-5.909, respectively).


CONCLUSIONS
Accumulation of cell cycle alterations represents a prognostic indicator in localized soft tissue leiomyosarcoma, and in particular altered p16/p53 expression is associated with an unfavorable prognosis. This may help the clinical management of patients with leiomyosarcomas.
Panelos
John
J
Department of Human Pathology and Oncology, University of Florence Medical School, Florence, Italy.
Beltrami
Giovanni
G
Scoccianti
Guido
G
Capanna
Rodolfo
R
Paglierani
Milena
M
Pepi
Monica
M
Massi
Daniela
D
Franchi
Alessandro
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D016193:G1 Phase; D006801:Humans; D007124:Immunoenzyme Techniques; D007890:Leiomyosarcoma / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D012983:Soft Tissue Neoplasms / Q000378:metabolism* / Q000473:pathology*; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1