In the United States, 39,200 deaths from prostate cancer and 184,500 new cases were reported in 1998, compared to 41,400 deaths from prostate cancer and 317,000 new cases in 1996. This means that the death rate of prostate cancer has begun to decline in the United States. Prostate cancer is characterized by a high incidence of latent cancer, ranging from 30% at age 50 to 40% to 80% at age 60 or older, while the clinical incidence is only 1.05%.
The incidence of latent cancer (clinically asymptomatic tumors detected by TURP) is not considered to be treated in the past and rarely develops within 5 years after detection, but after 10 years, 10% to 20% of the tumors develop into clinical prostate cancer, indicating that we know very little about the nature of prostate cancer, a large number of hidden prostate cancers are not detected, and there is a lack of in-depth understanding of its biological behavior and developmental tendency. Therefore, there is a need to find more sensitive methods to detect prostate cancer early and to predict its development.
Wolk (1998) suggested that insulin-like growth factor-1 (IGF-1) may be a risk factor for prostate cancer, and those with increased IGF-1 should be alerted to the development of prostate cancer, while those with mutations in BRCA2 have a 4- to 5-fold higher risk of prostate cancer than normal individuals, and PIN (prostatici
ntraepithelial neoplasia) is a newly proposed lesion that may be a predecessor of prostate cancer and is being extensively studied.
Prostate cancer is a disease of the elderly and rarely occurs before the age of 50. The clinical presentation of patients with prostate cancer is variable and its natural progression is unpredictable. Most prostate cancers occur in the periphery of the gland, away from the urethra, so early patients rarely cause symptoms.
Once the symptoms appear, it means that it is already in advanced stage or metastasis. If prostate cancer invades the urethra or bladder neck, it may cause obstructive symptoms, such as slow urination, thin urine line, difficult urination or irritation symptoms, such as frequent urination, nocturia, urinary urgency, urgent urinary incontinence, etc. Hematuria is also more common. If the tumor invades the ejaculatory duct, it may cause hematospermia and decrease in semen volume. The presence of impotence may indicate that the tumor has broken through the envelope and invaded the branches of the pelvic plexus of the penile corpus cavernosum.
Metastatic lesions may cause bone pain and anemia due to bone marrow damage; pelvic lymph node metastasis and iliac vein compression may cause lower limb edema; spinal metastasis and spinal cord compression may cause paraplegia and urinary retention; ureteral compression may cause hydronephrosis, oliguria or uremia; rectal compression may cause difficulty in defecation; cancer cells may also spread along the lymphatic tissue of ureter, causing malignant retroperitoneal fibrosis and, in a few cases, even DIC. The occurrence of DIC may be related to the activity of PSA protease.
Many patients present to the doctor with metastatic symptoms without symptoms caused by the primary prostate lesion.
The diagnosis of prostate cancer is determined by rectal examination (DRE), PSA or rectal ultrasound needle biopsy. PSA has been used clinically since 1987, and since the adoption of PSA for the diagnosis of prostate cancer, the number of patients with advanced cancer has been greatly reduced, and those who seek treatment for obstruction, urinary retention and pain are rare. However, the routine use of DRE and PSA to screen asymptomatic patients for early detection of tumors and to reduce mortality has been debated. Both the American Institute of Cancer Research and the American Urological Association advocate DRE and PSA in asymptomatic men >50 years of age because
(1) Early diagnosis and timely treatment can reduce mortality, and advanced prostate cancer is now incurable;
(2) simple DRE + PSA can detect tumors confined to the prostate, allowing for effective treatment. Opponents argue that early detection may be detrimental to the patient population on the grounds that there is a lack of objective evidence that surgical treatment of early stage patients has significantly different outcomes than non-surgical treatment;
(3) PSA may cause a large number of unnecessary tests, and screening has not been shown to reduce mortality from early prostate cancer;
(4) The comorbidities that occur during treatment would be substantial. The lack of a well-designed randomized control study has made it difficult to answer these questions with certainty. Furthermore, the tumors identified by PSA screening may be slow-growing, biologically insignificant tumors that are not harmful to the patient and do not cause death. Screening, surgery and the psychological and financial burden may cause unnecessary damage to the patient.
Most of the patients with prostate cancer have already metastasized by the time they come to the hospital with clinical symptoms, resulting in patients losing the chance to be cured. Recently, the diagnosis of prostate cancer is based on the measurement of PSA, combined with DRE, rectal ultrasound and biopsy, and its detection rate has increased by 70% compared to that before PSA was used, and it has doubled for early prostate cancer confined to the prostate, and as a result, the number of patients operated has increased greatly.
In 1992, the American Society for Staging of Cancer designated this type of tumor as stage T1c (B0) prostate cancer.
In 1988, Oesterling et al. performed radical prostatectomy in only 14 patients with T1c, while in 1991, radical prostatectomy was performed in 118 patients with stage T1c tumors, an increase of 734%, while only 94% more patients with stages T2a and T2b underwent radical prostatectomy during the same period, indicating that more patients were diagnosed early and treated through PSA screening tests. Treatment.
In a comprehensive review of 208 patients who underwent surgery from 1988 to 1991, Oesterling found that all 208 patients had normal DREs, normal prostate surfaces, no nodules, and no asymmetries, using the Tandem method of PSA testing. The rectal ultrasound was normal in 102 patients (49%), and hypoechoic area lesions were seen in 105 patients. All patients were systematically biopsied and all hypoechoic areas were biopsied, and the biopsy pathology was diagnosed as prostate cancer.
Radical prostatectomy was performed in 208 patients, and the resected prostate specimens were carefully examined postoperatively, noting whether there was penetration of the prostate envelope, whether the seminal vesicles and pelvic lymph nodes were involved, and especially the cut edges were examined for cancer infiltration. Also 208 T2a and T2b specimens were used as controls without selection. Among them, 148 cases were T2a and 60 cases were T2b tumors. The results showed that the PSA of the tumors in the T1c group was higher than that of the T2a and T2b, and the prostate in the T1c group was larger than that of the T2a and T2b groups.
In T1c group with PSA greater than 10ng/ml, 60 cases had tumors beyond the envelope; in T2a and T2b groups, 37 cases had tumors penetrating the envelope with PSA greater than 10ng/ml; 34% of T1c and 25% of T2a and T2b were involved in the cutting edge; 6 cases in T1c group had pelvic lymph node metastasis and 14 cases invaded the seminal vesicles. The above information indicates that the biological behavior of early stage T1c prostate cancer, which cannot be detected by clinical DRE, is basically similar to that of T2a and T2b, and belongs to clinical prostate cancer rather than latent cancer. although T1c tumors are detected early, postoperative pathological examination still shows that a few patients have tumors that have penetrated the peritoneum and invaded the seminal vesicles or even have pelvic lymph node metastasis. This indicates that the early diagnosis of tumor still needs to be further improved.
Walsh (1997) reported 240 cases of postoperative pathological examination of T1c stage tumors from 1994 to 1996, and found that 29% of the tumors were about 0.2-0.5 cm3 in size, which might belong to tumors of no clinical significance, and the surgical significance was not significant, which is also a topic to be solved. The problems related to the diagnosis of prostate cancer are described as follows.
I. Prostate specific antigen (PSA)
PSA has become the most sensitive tumor marker for prostate cancer and plays an important role in screening, clinical staging, efficacy detection and prognosis.
PSA is a kinin release enzyme family protein, a serine protease, produced by the prostate epithelium, the concentration in semen is high, which can make semen clot hydrolysis, liquefaction, function and male fertility, while the concentration in serum is low, the gene of PSA is in chromosome 19, the DNA sequence has been basically completed. PSA in serum occurs in both bound and unbound forms.
Most serum PSA is bound to protease antagonists such as α1-anti-chymotrypsin (ACT) or α2-macroglobulin (MG), and much more serum PSA is bound to protease inhibitors than unbound PSA, with only 10% to 20% free PSA, with free PSA + PSA-ACT representing total PSA.
The bound PSA in serum is too large a molecule to be filtered through the glomerulus and needs to be excreted through the liver. The half-life of PSA in serum, measured by prostate tissue removal, is 2 to 3 days. After radical prostate cancer surgery, PSA often takes several weeks to become unmeasurable. The clearance of free PSA, with a shorter half-life of 2 to 3 hours, can be filtered through the glomerulus.
PSA expression is strongly influenced by androgens, and serum PSA is not measured until after the increase in LH and testosterone during puberty.
PSA can diffuse into the prostate tissue and then enter the bloodstream. A prostate biopsy can cause PSA to enter the bloodstream, and it usually takes 4 weeks for PSA to return to baseline levels.
A DRE performed in an outpatient setting can increase PSA, but the increase is very weak, not clinically significant, and rarely causes a false positive. Measuring 100 male patients aged 20-30 years and having the patients perform a PSA test on the 2nd day after seminal emission revealed a significant decrease in PSA, indicating that the PSA values should be interpreted in younger patients in relation to the patient’s sexual activity.
Prostatitis, prostate enlargement and prostate cancer are important factors affecting PSA serum levels. Increased PSA indicates prostate disease, but not all people with prostate disease have increased PSA, and increased PSA is not specific for cancer.
Prostate surgery, orchiectomy, LHRH-A, Paulownia therapy, and radiation therapy for prostate cancer can all reduce serum PSA levels. PSA decreases by 50% after 12 months of applying the 5α-reductase inhibitor Paulownia. Patients using Paulownia should have their PSA values checked before using the drug and should be reviewed periodically. If PSA fails to decrease by 50% or PSA conversely increases during the use of Paulownia, occult prostate cancer should be suspected.
The PSA is usually measured using the Tandem method with a base set at 0.0 to 3.99 ng/ml. routine use of PSA measurement increases the early detection of prostate cancer and tumors still confined to the prostate envelope. catalona (1999) advocates setting the PSA base at 2.5 ng/ml, which allows for the detection of more cancerous tumors. In the screening population, the chance of detecting cancer by biopsy was 1/50 for those with PSA 4ng/ml, 1/4 for those with 4-10ng/ml, and 1/2 or 2/3 for those with >10ng/ml.
For those with high PSA, biopsy should be performed regardless of whether DRE is normal or not. It is not advisable to perform only PSA but not DRE examination. Because 25% of patients have PSA <4ng/ml, it is best to combine PSA with DRE. In a group of 6630 people, 264 cases of prostate cancer were found after screening, and if only PSA was performed, 18% of the tumors could be missed. In contrast, 45% of tumors were missed when DRE alone was performed to determine the presence of a tumor, and the tumor found with the combination of DRE and PSA was not necessarily the same tumor.
The PSA assay can advance the diagnosis of prostate cancer by 4 years. A group of 48 patients with PSA assay were finally confirmed by pathology.
PSA measurement can also be used to test the efficacy of treatment and determine prognosis. The PSA measurement is not specific for the diagnosis of prostate cancer, but BPH, inflammatory lesions and infarction can increase PSA, so it is of practical significance to make a differential diagnosis based on PSA changes in clinical practice.
1. PSA density: Most patients with increased PSA (80%) have PSA between 4.0 and 10.0 ng/ml. Since the incidence of BPH in the population is higher than that of prostate cancer, most of the increased patients are caused by BPH. Early prostate cancer can directly increase PSA, and the prostate volume has less influence, while BPH increases PSA mainly through the increase in volume, measuring PSA and prostate volume to obtain PSA density, PSAD = PSA/prostate volume, DRE, TRUS and biopsy should be performed when PSAD 0.15, and it is believed that PSAD has improved accuracy than PSA in identifying BPH from prostate cancer.
The opposing view is that the epithelium secreting PSA is not always equal in prostates of equal size, and that the morphology of the prostate is variable, which can affect the determination of prostate size. In BPH, PSA is mainly from the migratory zone rather than the peripheral zone, and there is no accurate method of measuring the amount of epithelium and its secretion of PSA, so PSAD is not considered superior to PSA determination. It is possible that measuring the serum PSA/prostate migratory zone ratio would be more helpful for diagnosis.
2. PSA rate: PSA increases significantly faster in patients with prostate cancer than in those with benign prostate lesions. An annual increase of 0.75ng/ml in PSA is a characteristic of prostate cancer and can be detected before prostate cancer is detected and PSA has not yet increased. Numerous screening data have demonstrated that if the PSA rate exceeds 0.75 ng/ml per year, prostate cancer can be detected in 47% of patients. The accuracy can be higher if 3 repeated measurements are performed to determine the average velocity change.
3. Molecular form of PSA: PSA is present in serum in both bound and unbound molecular forms. Measuring the molecular form of PSA can improve the ability of PSA to predict prostate cancer. The majority of PSA in serum of prostate cancer patients consists of PSA bound to ACT, which is over 90%, significantly higher than that of prostate hyperplasia, and it is possible that cancer cells can produce more ACT, while serum of prostate hyperplasia patients The free PSA (f-PSA) is higher in patients with prostate hyperplasia than in prostate cancer. If the free PSA/total PSA ratio is ≤0.18, the differential diagnosis between cancer and non-cancer can be significantly improved.
Recently, f-PSA has been found to be more reliable than total PSA for screening prostate cancer. The serum PSA-ACT complex is significantly higher in patients with prostate cancer than in BPH, while f-PSA is significantly higher in patients with BPH up to 30% and only 15% or less in patients with prostate cancer. The specificity of f-PSA is 86%, which is significantly better than PSA and PSAD.
F/T percentage can improve the specificity of PSA and reduce unnecessary biopsies in many hyperplastic patients. F/T percentage of 10%-25% should be used for prostate biopsy, F/T>25% is very unlikely for prostate cancer (10%) and F/T<10% is very likely for prostate cancer (80%). However, some authors hold the opposite opinion and believe that there is no superiority compared to PSA.
Most research work has confirmed that serum PSA correlates with clinical and pathological staging, but it is still difficult to obtain correct staging by PSA levels alone.
Because there is duplication of PSA in different staging, PSA correlates with the volume of the tumor, but other factors can affect the overall PSA level, especially the volume of BPH. BPH tissue can provide serum PSA 0.15 ng/ml per gram, but it is almost impossible to accurately determine how much serum PSA BPH can provide for a given individual. PSA comes from the prostate epithelium, and in In BPH tissue, epithelium and stroma are not fixed, and there is no exact non-invasive method to distinguish between epithelium and stroma in BPH. Partin (1990) has reported an inverse decrease in PSA production per gram of tumor tissue in advanced, high-grade large tumors.
However, as a general rule, in most patients (70% to 80%) with PSA 4.0ng/ml, the tumor is confined to the prostate, 50% of those with PSA greater than 10.0ng/ml have penetrated the envelope, and 75% of those with PSA levels greater than 50ng/ml have pelvic lymph node metastases.
II. Prostate-specific membrane antigen (PSM)
PSM is a type II membrane glycoprotein with a length of 2.65 kb and a relative molecular mass of 10,000, encoding 750 amino acids, with 19 amino acids in the cytoplasm and 24 amino acids in the transmembrane. PSM is a type II membrane glycoprotein, 2.65 kb long, with a relative molecular mass of 10,000 and encoding 750 amino acids, 19 amino acids in the cytoplasm, 24 amino acids in the transmembrane part, and 707 amino acids in the rest of the cell.
PSM expression is significantly increased after androgen removal, so it is considered to be used to detect patients with poor response to androgen removal, and PSM expression is increased in patients with metastatic prostate cancer and poor response to hormone therapy. bFGF can increase PSM expression by 100%.
In contrast, in the normal prostate, PSM′ is expressed more often (PSM:PSM′, 1:10), and in BPH, the two are equally expressed. ～The PSM to PSM′ ratio also varies from 0.075 to 0.45 for normal prostate, 0.75 to 1.60 for BPH, and 3 to 6 for prostate cancer, so it can also be used to observe the course of the disease or to diagnose it.
The anti-PSM monoclonal antibody named Cyt-356 is now commonly used to diagnose prostate cancer metastasis, the sensitivity of CT in diagnosing prostate cancer metastasis is <20%, which is similar to MRI. ～It is 30% to 40% more sensitive than CT.
The PSM mRNA test can help to detect clinically unknown early stage prostate cancer metastasis and determine whether the tumor is recurrent, but whether PSM can represent living cancer cells and whether it means that the patient has lost the chance of treatment once it appears is not certain and needs to continue clinical observation. Using RT-PCR, by amplifying a 10bp fragment of PSAmRNA, cancer cells in the blood that can make PSA can also be measured. Early detection of prostate cancer beyond the envelope was found, and the accuracy of diagnosing envelope penetration was 84.4% when compared with postoperative pathology. 71.9% in those with seminal vesicle involvement.
If the preoperative PSA is 10ng/ml and the RT-PCR is positive, the tumor has surpassed the envelope in 100% of the patients. Therefore, it is said that the RT-PCR method is the best method nowadays to understand whether the prostate cancer is confined within the prostate envelope or has broken through the envelope, which is called molecular staging.
DRE
DRE is routinely used to examine the localization of prostate cancer. Because of the subjectivity of DRE, pathological examination often reveals that DRE is under-staged or over-staged. In a group of 565 patients with DRE diagnosis of T2 organ-confined tumor, 52% were confined to the prostate, 31% had penetrated the peritoneum, and 17% had seminal vesicle involvement or lymph node metastasis, indicating a large error in DRE staging.
DRE is the first step in diagnosing prostate cancer, which can reveal the size, hardness, bilateral symmetry, and the presence of irregular hard nodes of the prostate. Advanced prostate cancer is hard as a rock, with huge masses, fixed and unclear borders, and not palpable above, so there is no difficulty in diagnosis, but there are a few patients with normal texture, and it is not easy to distinguish from BPH.
IV. Transrectal ultrasound examination
TRUS has the problem that most of the lesions found in the hypoechoic area are not cancerous, and nearly 50% of tumors of 1 cm size that cannot be reached by fingers are often not detected by TRUS, although those with cancerous hypoechoic lesions are twice as high as those in the isoechoic area, and if only biopsy is performed on the hypoechoic area, 25% to 50% of the cancerous tumors may be missed, so those suspected to have tumors or increased PSA by DRE should be Therefore, biopsy should be performed for any tumor suspected by DRE or PSA elevation.
Since TRUS is not accurate enough for early tumor localization, it should not be used as a first-line screening tool.
V. Prostate biopsy
The clinical information provided by DRE, serum PSA or TRUS, and finally pathological histological examination are required to determine prostate cancer. Nowadays, systematic 6-point biopsy and random biopsy with 18-gauge needles (much smaller than previous models) are commonly used, and complications such as infection and bleeding are significantly reduced, generally less than 2%. Needle penetration biopsy is not only used for diagnosis, but also has important significance in grading and staging of cancer, and observation of disease after radiotherapy.
However, this method still has some limitations. According to statistics, the detection rate of traditional systematic 6-point biopsy is only 20%-30%; Keeth reported that 24% (104/427) of those with negative first biopsy were found to have tumor on re-biopsy due to persistent increase in PSA; Lui et al. reported that up to 38% (72/187) of those with positive re-biopsy, and 28% (53/187) of those with positive re-biopsy by other authors. 53/187) were positive, of which 10% were located in the migratory zone. Therefore, systematic 6-point biopsy is not considered an ideal method and needs to be improved.
Bauer et al. (1999) used a three-dimensional computer simulated prostate model to perform a lateral prostate biopsy with 5 zones instead of 6-point biopsy, and the detection rate was 99.0% (199/201), whereas the 6-point method detected only 72.6%. Most of the tumors were located posteriorly and laterally. It should be considered as a major improvement in prostate biopsy method.
After the diagnosis of prostate cancer is clear, the extent of the lesion, i.e., staging, should be further understood for two purposes.
(1) to evaluate the prognosis of the tumor.
(2) to adopt reasonable treatment according to the extent of the lesion, to understand whether the tumor is confined to the prostate gland, or has penetrated the envelope, invaded the seminal vesicles, or has pelvic lymph nodes and distant metastases, etc. Once the tumor has gone beyond the envelope, it is difficult to cure.
Generally clinical staging is often lower than postoperative pathological staging. Taking the above T1c stage tumor as an example, no tumor was found in DRE and TRUS, but 60 cases were found to have exceeded the envelope postoperatively, and a few had pelvic lymph node metastasis, the combination of clinical and pathological can obtain a more in-depth understanding of the biological behavior of prostate cancer. In general, the PSA, grading, staging and imaging can give a preliminary understanding of the extent of tumor lesions, but they are not accurate enough.
VI. Radioimmunoimaging
The application of 131Ⅰ-human seminal plasma protein antibody radioimmunoimmunoassay can show prostate cancer and metastatic lesions. Hao Xiao Ke et al. (1993) obtained tumor localization images according to the application of SPECT and dual nuclide tracing and computerized subtraction techniques.
The best imaging time was 96 hours, and 66 of 69 prostate cancer cases were positive, with a positivity rate of 95.7% and a minimum tumor diameter of 0.5 cm. The sensitivity of CyT-356 is 30%-40% higher than that of CT.
VII. Diagnostic imaging
MRI, CT, TRUS, IVU, etc. have been used as staging tests for prostate cancer. The staging of prostate cancer must be able to distinguish whether the tumor is confined to the prostate or has metastasized to the outside, which is difficult to achieve with the commonly used imaging tests. In general, CT cannot show the peripheral zone, central zone and metastatic zone of the prostate, so the diagnostic rate is significantly lower than that of MRI. However, its sensitivity is similar to that of MRI for the invasion of tumor adjacent tissues and organs and pelvic lymph nodes.
The purpose of CT examination is to stage the tumor, not to diagnose it. MRI has good tissue resolution and three-dimensional imaging, and is superior to other imaging examinations for the prostate. However, the MRI signal in the central and migratory zones of BPH is similar to that of prostate cancer, and the low signal in the T2-weighted peripheral zone is not specific for prostate cancer, so both CT and MRI lack the role of diagnosing early prostate cancer and are only helpful for staging. When the tumor compresses the ureter causing obstruction and the renal function is impaired, magnetic resonance urography can clearly visualize the urinary tract without the limitation of renal function, which is better than IVU.
Parifar (1998) reported the use of 3 dimensional proton magnetic sp ectroscopic
imaging (MRSI) to localize all prostate chemistry and to detect the levels of choline and citrate metabolites, with high citrate and low choline in benign lesions and low citrate and high choline in prostate cancer, which were computerized.
The spatial resolution is 0.24-0.70 cm3, so even very small tumors can be detected, which is initially considered more reliable than biopsy.
Diagnosis of prostate cancer bone metastasis
The sensitivity of radionuclide diagnosis of bone metastasis is very high, with a false negative rate of <1%, and bone metastasis can be detected 6 to 18 months before X-ray.
However, the specificity is lower than that of X-ray examination, and it is now considered that bone scan is not necessary for PSA<10ng/ml, and the negative prediction rate is as high as 99.7%.
In 7 patients with serum PSA below 8.0ng/ml, none of them had a positive bone scan and the false negative rate was 0. If the base value of PSA was set at <20ng/ml, 852 patients had a positive bone scan.
If the base value of PSA is set at < 20ng/ml, only 7 cases of bone metastases were found in 852 patients (0.8%), so it is considered that newly diagnosed untreated patients with no bone metastases and low PSA may not be treated.
Therefore, it is considered that newly diagnosed untreated patients with no bone metastasis symptoms and low PSA may not be scanned for bone metastasis, which can also save a lot of money.
The expression of PMA and PSA mRNA in blood was determined by RT-PCR according to the serum PSA level, and a three-dimensional computational
In addition, the use of a three-dimensional computational model of the prostate gland, the use of an external posterior prostate zone 5 biopsy instead of a 6-point biopsy, and the recently investigated three-dimensional proton magnetic resonance spectroscopy technique will greatly improve the diagnosis of early prostate cancer.