ReviewSignificance of micrometastases in prostate cancer
Introduction
Of several clinicopathological parameters, pelvic lymph node metastasis has been regarded as the most important factor predicting disease recurrence in patients with clinically localized prostate cancer who underwent radical prostatectomy. Patients with organ-confined prostate cancer have a favorable prognosis and a low-risk of disease recurrence after radical prostatectomy, while biochemical recurrence, characterized by a continuously increasing serum prostate-specific antigen (PSA) value, is observed in approximately 10% of patients in this subgroup [1], [2], [3], [4], which is often associated with the eventual development of clinically significant metastases. It is, thus, possible that micrometastatic disease is already present in some of these patients at the time of surgery. Since routine microscopic examination of dissected lymph node specimens can miss small cancer foci [5], [6], [7], this may partially account for the presence of histologically undetectable micrometastases in the pelvic lymph nodes. In fact, a number of studies have demonstrated that higher sensitivity for detecting micrometastatic cancer cells in surgically removed pelvic lymph nodes at radical prostatectomy can be achieved by several molecular and histolopathological techniques targeting genes specifically expressed in the prostate [8], [9], [10], [11], [12], [13]. We also reported the usefulness of a fully competitive reverse transcriptase-polymerase chain reaction (RT-PCR) targeting prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) genes for the detection of micrometastatic prostate cancer cells in the pelvic lymph nodes [14], [15]. To date, unfortunately, none of these methods have been introduced into clinical practice due to various limitations, such as a high false–positive rates and complicated procedures. In addition to technical aspects for detecting micrometastatic cancer cells, it would be important to characterize the clinical significance of identifying such occult disease. However, it remains controversial whether the presence of micrometastatic cancer cells in the pelvic lymph nodes really has an adverse impact on the prognosis of patients with prostate cancer.
Considering these findings, this article reviews recent progress in the detection of micrometastases in pelvic lymph nodes obtained from patients with prostate cancer, focusing on the following topics: (1) comparison among several techniques for detecting micrometastases; (2) suitable marker genes targeted by these techniques; (3) clinical significance of micrometastases detected in the pelvic nodes; (4) limitations of these techniques; and (5) application of these techniques to peripheral blood or bone marrow.
Section snippets
RT-PCR
The main problems in conventional histopathological evaluation of lymph node specimens are sampling error and poor sensitivity for detecting small tumor foci; therefore, a number of investigators have applied RT-PCR assay to the detection of micrometastatic cancer cells in order to overcome the limitations of routine pathological examinations [16], [17]. Theoretically, RT-PCR assay is suitable for the identification of minute amounts of mRNA coding for proteins specifically expressed in the
Target genes for detecting micrometastatic prostate cancer cells
There are several genes that are rarely expressed outside the prostate gland [33], [34], [35], [36], [37], [38], that thus have the potential to be optimal candidates as specific markers for the detection of prostate cancer cells. In fact, PSA and/or PSMA have traditionally been used as target genes for detecting micrometastases of prostate cancer, since expression of the PSA and PSMA genes is exclusively restricted to prostate epithelial cells, and this high specificity makes it possible to
Clinical significance of micrometastases in patients with prostate cancer
To introduce novel molecular and histological techniques for detecting micrometastases in patients with prostate cancer, it seems to be critical to determine whether the outcomes of these assays correlate with clinicopathological findings, including the prognosis. It would be difficult to fairly evaluate the outcomes of these assays, since several kinds of assays were used by various research groups, and each assay consisted of complex, multistage technical steps, and even in the same assay,
Technical limitations for detecting micrometastases
There are a number of issues to be overcome associated with the detection of micrometastases by novel molecular and immunohistochemical assays before these assays can be introduced into urological clinical practice. The ideal assay would detect the presence of a critical number of prostate cancer cells correlating with eventual disease progression based on a procedure that is as simple as possible.
Current pathological examinations of dissected lymph nodes stained with hematoxylin and eosin have
Application of novel techniques for detecting micrometastases to peripheral blood or bone marrow
In this review, we mainly focused on the detection of micrometastases in pelvic lymph nodes from patients with localized prostate cancer, while intensive studies have also been carried out for identifying disseminated prostate cancer cells to peripheral blood or bone marrow [18], [46], [47], [48], [49], [50], [51], [52].
In 1994, Katz et al. collected blood samples from 319 patients prior to radical prostatectomy and analyzed these using an RT-PCR targeting PSA. They reported that 16% of
Conclusion
Considering the outcomes of analyzing the utility of novel molecular and immunohistochemical assays for the detection of micrometastatic prostate cancer cells, positive findings using these assays may have relevance to the clinical course of patients following radical prostatectomy. However, the optimization of these novel assays is still required to further enhance the sensitivity keeping with reasonable specificity in order to avoid both false–positive and false–negative results as much as
Conflict of interest statement
None declared.
References (52)
- et al.
Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years
J Urol
(1994) - et al.
Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy for prostate cancer: intermediate-term results
J Urol
(1998) - et al.
Pathologic findings at radical prostatectomy: risk factors for failure and death
Urol Oncol
(2007) - et al.
Molecular quantification and mapping of lymph-node micrometastases in cervical cancer
Lancet
(2001) - et al.
The influence of serial sections, immunohistochemistry, and extension of pelvic lymph node dissection on the lymph node status in clinically localized prostate cancer
Eur Urol
(2003) - et al.
Detection of micrometastatic prostate cancer cells in the lymph nodes by reverse transcriptase polymerase chain reaction is predictive of biochemical recurrence in pathological stage T2 prostate cancer
J Urol
(2000) - et al.
Molecular staging of prostate cancer with the use of an enhanced reverse transcriptase-PCR assay
Urology
(1994) - et al.
Real-time reverse transcriptase-polymerase chain reaction for intraoperative diagnosis of lymph node micrometastasis: clinical application for cervical lymph node dissection in esophageal cancers
Surgery
(2002) - et al.
Incidence of occult lymph node metastases in pathological stage C (pT3N0) prostate cancer
J Urol
(1995) - et al.
Circulating tumor cells predict survival in patients with metastatic prostate cancer
Urology
(2005)