Prostate cancer is the malignancy most likely to develop bone metastasis. About 84% of bone metastases are found at autopsy. Early and accurate diagnosis of bone metastasis is decisive for the staging and treatment plan of prostate cancer, and also has an important significance for the prognosis of the tumor. The most commonly used methods are SPECT bone scan, which can detect metastases 6 to 18 months before the appearance of lesions on X-ray.
Although the sensitivity of bone scan is high, it lacks specificity. Therefore, many scholars have established a series of new detection techniques for early diagnosis.
1.1 PET imaging
PET (positron emission tomography), or positron emission tomography. As early as in the 1930s, Warburg demonstrated that anaerobic metabolism was strong in cancer cells and anaerobic enzymolysis of glucose was increased, resulting in higher utilization and uptake of glucose in tumor cells than in normal cells. The tracer 18F-DG (18F-2-deoxyglucose) is phosphorylated by the action of hexokinase in tumor cells to form 6-P-18F-DG, and then it no longer participates in further metabolism and glycogen synthesis, but is taken up by tumor cells and stays in the cells. This metabolic process provides a good opportunity for tumor PET imaging.
Shreve [5] performed PET imaging of 34 metastatic prostate cancers and found abnormal concentrations of 18F-DG in bone, lymph nodes or liver in at least 20 cases. In untreated patients, 133 lesions were identified, of which 131 were confirmed as metastases and 2 were false positives, with a positive predictive value of 98%. 71 positive bone scans were negative on 18F-DG imaging, of which 7 were confirmed as benign lesions. PET has a high specificity for the diagnosis of bone and soft tissue prostate cancer metastases, but its sensitivity is lower than that of whole-body bone scan, which is only 65%.
1.2 99mTc-colloid imaging method
99mTc-labeled colloidal particles prepared with human albumin can be used as a bone marrow imaging drug. Using ν-photographic technique, the metastatic foci of tumor are shown to be replaced by tumor tissue, forming a “pan” radioactive defect area. Lentle et al. used this method to examine 200 patients and found 16 cases with bone metastases, of which 4 cases were negative on radiographs and 2 cases were negative on conventional bone imaging. 99mTc-colloid imaging is simple and easy to perform, but its disadvantage is that there is a certain degree of interference with non-specific imaging.
1.3 Radioimmunoassay (RII)
Radioimmunoimaging (RII) is a tumor localization diagnostic technique using radionuclide-labeled antibodies against tumors and their associated antigens as tumor-positive visualizing agents. Anti-granulocyte monoclonal antibodies have both the ability to bind to non-specific cross-antigens
(NCA) and anti-CEA properties. Anti-NCA monoclonal antibodies bind well to these cells, as all granulocytes and bone marrow cells have NCA on their surface. The number of bone marrow granulocytes is 50 to 100 times higher than that of peripheral blood. Rilinger et al. used 99mTc-labeled anti-granulocyte monoclonal antibody BW 250/183 for bone marrow imaging and found 57 metastases in 23 patients with solid tumors, whereas only 40 metastases were detected with 99mTC colloid.
Munz et al. concluded that this method was superior to conventional bone scan and MRI in detecting bone marrow metastases, and was simple and economical. However, the disadvantage is that the mouse-derived monoclonal antibody may produce autoantibodies after entering the body, which may cause allergic reactions or affect the effect of radioimmunoassay. ν-Sm is a new marker for prostate cancer, which is similar to PSA in immunochemical structure and has higher specificity than PSA in the diagnosis of prostate cancer. The use of “131I-ν-Sm antibody for radioimmunoimmunoassay can show prostate cancer and metastatic lesions.
The tumor localization image was obtained by Hao (1993) based on the use of SPECT and dual nuclide tracing and computerized subtraction techniques. The minimum tumor diameter detected was 0.5 cm, and 13 cases of pelvic lymph nodes and bone metastases were detected at the same time. Wynant (1991) used 111In-labeled prostate-specific membrane antigen (PSM) monoclonal antibody (CYT-356) to diagnose prostate cancer bone metastases by radioimmunoassay, and the positive rate was 55%. Recently, Kahn and Babaion also used the same method to detect potential recurrent prostate cancer lesions and metastases, which provides a new diagnostic tool for prostate cancer.
2. Application of immunohistochemical techniques
The relationship between keratin and prostate-specific antigen detection and micro-metastasis of prostate cancer bone marrow has been studied more in recent years. Keratin is a marker of epithelial cell differentiation, and it exists in all kinds of epithelial cells in the body. Therefore, keratin immunohistochemical staining can be used to determine bone marrow micrometastases in tumors of epithelial origin.
Oberneder et al. used keratin 18 (CK18) monoclonal antibody to detect bone marrow in 84 patients with prostate cancer. CK18-positive tumor cells were detected in 33% of patients with stage N0M0 prostate cancer with a sensitivity of 1 CK18-positive cell found in 8×105 bone marrow cells. The control group of 12 patients with prostate hyperplasia were negative. no false positive results were found in the larger control group of Schlimok et al.
The prostate specific antigen (PSA) is a glycoprotein secreted by prostate epithelial cells and has tissue specificity.Wood et al. used PSA monoclonal antibody to detect bone marrow micrometastases in 55 prostate cancer patients (45 with clinically limited tumors and negative bone scans). 19 were positive and 5 with prostate hyperplasia were negative. However, the sensitivity and specificity of immunohistochemistry for detecting micro-metastases in the bone marrow of prostate cancer need to be improved. The quality control in the study is also very important.
3. Application of PCR technique
RT-PCR (Reverse Transcription-Polymerase Chain Reaction) is a newly developed technique. RT-PCR analysis is a highly sensitive and specific method for detecting occult metastases.
Compared with conventional immunohistochemical analysis, it is economical and relatively simple, with much higher sensitivity and specificity. Wood et al. used RT-PCR to detect PSA mRNA and immunohistochemical staining with PSA monoclonal antibody to detect metastatic cancer cells in the bone marrow of prostate cancer patients. The results showed that 51% of the 55 patients had tumor cells in the bone marrow. 43 patients with radical prostate surgery and no clinical metastases had micro-metastases in the bone marrow in 19 patients (44%).
Of the 29 patients with positive PCR, 24 had positive immunohistochemical staining. The sensitivity of this method was shown to be as high as finding one prostate cell out of 106 lymphocytes in Wood’s study.
The sensitivity of PCR technique is high, but it should be prevented from false positives. The application of these new methods in the detection of prostate cancer bone metastases will help to understand the biological characteristics of prostate cancer and provide more information for clinical staging, proper treatment planning and prognosis.