Ann Thorac Surg 2003;75:1732-1733
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
Invited commentary
W. Roy Smythe, MDa
a Department of Thoracic Molecular Oncology, MD Anderson Cancer Center, The University of Texas, 1515 Holcombe BlvdHouston, TX 77030, USA
e-mail: rsmythe{at}mdanderson.org
This article by Haga and colleagues evaluates the prognostic significance of Ki-67 immunohistochemistry in patients with resected early stage nonsmall cell lung carcinoma. Although many have addressed the question of prognostic significance of this protein in solid tumors, this manuscript makes the novel association of Ki-67 expression, smoking status, and prognosis.
The use of immunohistochemistry for prognostic purposes is by no means novel, but in most cases, the function and oncologic importance of the protein being evaluated is known (eg p53 and Rb). Interestingly, although a myriad of studies have evaluated expression of this protein in malignancy, little is known about the function of Ki-67. It is a very large (395 kDa) protein, and its localization in the cell is dynamic and cell cycle specific. It is associated with the dense fibrillary component of the nucleolus. Structure function analysis, which is developing rapidly in this era of proteomics, is of limited assistance as Ki-67 is not homologous to any other known protein. It is probably important for cellular proliferation, as antisense oligonucleotide inhibition of its expression inhibits proliferation. Various theories have been proposed regarding true function of this protein, including roles in cell cycle regulation, DNA organization, nucleolus structure maintenance, and ribosome synthesis.
The era of molecular pathology is upon us and will obviously augment the anatomic staging systems that we now ascribe to, but much work yet needs to be done. There are many inherent problems with immunohistochemistry, including sampling error, heterogeneity of expression, subjective evaluation, and antibody variability. Newer techniques, including comparative proteomics and rapid quantitative PCR analysis, may be of benefit in the association of gene and protein expression and prognosis in tumor specimens, and are being evaluated. Real-time in vivo assays would be helpful, whereby imaging methods are developed to both localize the tumor prior to resection and yield concomitant "whole tumor" biologic and prognostic information. There is no doubt that these efforts are vitally important in nonsmall cell lung carcinoma, where up to 25% of resected stage I "surgically cured" patients still succumb to recurrent disease. We must continue to work diligently in this area and to capitalize on the genomic information becoming available to identify new markers of prognosis. A full understanding of the biologic function of each marker will assist us in realistically assessing the ability to predict clinical outcomes and direct therapy, and possibly identify novel molecular and cellular therapeutic targets.
