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I. PRESENTATION
A. Subjective. Prostate cancer rarely causes symptoms early in the course of the disease as most of the adenocarcinomas arise in the periphery of the gland away from the urethra.
In the prostate-specific antigen (PSA) era, the most common finding is the absence of symptoms. The presence of symptoms due to prostate cancer often suggests locally advanced or metastatic disease. Growth of prostate cancer around or into the urethra, or involvement of bladder neck can result in decreased urinary force of stream, frequency, urgency, nocturia, or hematuria. However, many of these symptoms are not specific and may occur with benign prostatic hyperplasia and aging. Involvement of ejaculatory ducts can cause hemospermia, and extraprostatic disease involving the branches of pelvic plexus can cause erectile dysfunction (ED).
Metastatic disease can cause a wide variety of symptoms related to the sites of metastases. Bone is the favored site of metastasis, with pain being a common, and at times, debilitating symptom. Men with spinal metastases may live for years; therefore, careful and thoughtful serial histories and examinations are mandatory. The most devastating consequences of bone involvement are pain, fractures, and spinal cord or nerve root compression. Spinal cord compression is usually accompanied by back pain that is often made worse by coughing, sneezing, or straining (and other activities that increase intradural pressure). Unlike nonmalignant causes of back pain, the back pain of metastatic prostate cancer is usually worse at night. If a peripheral nerve is pinched by tumor, the back pain may radiate around to the front of the patient in the thorax or abdomen or down the legs. Patients with early spinal cord compression will have weakness, with progression to paralysis occurring, on the one hand, over a period of weeks to even months. On the other hand, late spinal cord compromise leads to loss of sensation distal to the level of metastasis, urinary retention, and incontinence in a matter of minutes to hours. The classic symptoms of cauda equina syndrome are low back pain, bilateral sciatica, sensory and motor deficits, including sacral and perianal anesthesia, and loss of sphincter control of bladder and anus. Delays in management result in permanent loss of sensation, motor function, and continence.
Fatigue is a prominent complaint of patients, but it may occur for very different reasons depending on the state of the tumor and the patient. If due to advanced or metastatic disease, it may be an indicator of bone marrow infiltration by tumor with associated anemia. Liver involvement occurs in only 15%, usually at the end of life. Hepatic metastases are usually due to poorly differentiated adenocarcinomas or to tumors with small cell (neuroendocrine) differentiation.
Androgen deprivation therapy (ADT) and/or chemotherapy can cause anemia, but the former is usually mild, whereas the latter may be moderate or severe. Lower limb edema can result from pelvic lymph node involvement, compression of iliac veins, and/or deep vein thrombosis (DVT).
Shortness of breath may be due to chemotherapy treatment, anemia, pulmonary embolism, and/or lung metastases, but the latter occurs late in only 15% of patients. Later in the course of the disease, older men complain of fatigue and gradually fail to thrive at home, with debilitating bone pain, weakened legs, decreased activity, poor appetite, weight loss, and other symptoms of advanced metastatic disease.
B. Objective. With the widespread use of PSA screening and early detection programs, the most common finding on examination of the prostate is the absence of findings. Despite the lead time bias that PSA screening introduces, physicians must be able to perform an excellent digital rectal examination (DRE) to diagnose and clinically stage localized prostate cancer. Attention should be directed to defining the presence or absence of a nodule and its location with respect to the right or left lobe and median raphe. Clearly, the absence of a nodule does not preclude the diagnosis of prostate cancer, and simply hardness of the prostate may indicate the presence of tumor. As patients become more obese, the DRE becomes more difficult to perform, but one should try to define extracapsular extension and/or involvement of the seminal vesicles. The sensitivity and specificity of the DRE is modest to poor, depending on the examiner, which can lead to both over- and underdiagnosis.
As with all cancer patients, the oncologist must do a careful, comprehensive physical examination, with special attention to signs of anemia, lymphadenopathy, bone tenderness, neuropathy, and lower extremity edema. For men treated with ADT, the testicular examination ought to show atrophy, whereas its absence should alert the physician that the patient does not have castrate levels of testosterone. Because of the potential for extended periods of good quality of life (QOL) and survival, even with metastatic disease, prostate cancer remains one of several neoplasms that physicians must rule out in the evaluation of carcinoma of unknown primary tumor.
II. WORKUP AND STAGING. Autopsy studies have shown localized prostate cancer in approximately 30% of men older than 50 years and 70% of men older than 80 years. However, with the availability of serum PSA and transrectal ultrasonogram-guided needle biopsy of the prostate, clinically organ-confined prostate cancer is increasingly diagnosed, with continuing uncertainty regarding the clinical significance of some tumors. Defining the grade of the tumor and anatomic stage are critical in understanding the prognosis and formulation of a treatment plan. Various predictive models (e.g., Partin table, Kattan nomograms) have been developed and are available for use in clinical practice for counseling patients and for planning a rational management plan. Most of these validated models include prognostic variables such as PSA, Gleason score, and clinical stage of the cancer.
A. Laboratory testing
1. PSA. PSA is a serum marker that is central to the diagnosis and management of prostate cancer. The use of PSA testing has helped to identify cases of prostate cancer that are or will become clinically significant, rather than simply identifying cases of cancer that are unlikely to be detected until autopsy. PSA is directly associated with tumor volume and clinical stage. Normal PSA ranges depend on factors such as age and race, and PSA level is affected by prostatic biopsy but not significantly by DREs.
Absolute PSA levels and the rate of change of those levels with respect to time can predict the likelihood of organ-confined disease and influence opinions on the likelihood of a cure. PSA levels greater than 10 µg/L are associated with increased risk for extracapsular extension. The positive predictive value for a PSA between 4 and 10 ng/mL in patients with normal DRE is only 30% approximately. To improve the performance of the PSA test, modifications, such as PSA velocity, PSA density, and free-to-total PSA ratio have been used. Some physicians advocate the use of free PSA versus bound PSA to quantify further the risk of cancer and need for biopsy; higher percentage free PSA levels are associated with more favorable histopathologic features in prostate tumors. A cutoff of 25% free PSA detects 95% of cancer while avoiding 20% of unnecessary biopsies.
PSA kinetics has been explored to improve PSA testing. A study showed men whose PSA level increased by more than 2.0 ng/mL during the year before diagnosis of prostate cancer were at high risk for cancer-specific death even if they had “favorable” clinical parameters (such as a PSA level <10 ng/mL and Gleason score <6 at diagnosis) and that they should undergo radical prostatectomy (RP). For these men, active surveillance may not be an appropriate option. Their increased risk also makes them candidates for enrollment in clinical trials examining various combination treatment strategies. Physicians must use caution when using such measures because men with tumors with Gleason scores of 8, 9, and 10 may be so poorly differentiated that they do not synthesize and secrete large amounts of PSA.
2. Complete blood count and chemistries. The laboratory workup should include a complete blood count and comprehensive metabolic panel. Widely metastatic disease may cause anemia or thrombocytopenia because of marrow infiltration, but most patients will have normal peripheral counts and normal chemistries at the time of diagnosis. Abnormal tests should prompt investigation, especially in patients thought to have only localized disease. For example, an elevated alkaline phosphatase may be due to bone metastases and, therefore, a bone scan should be done to rule out this possibility.
B. Imaging. Computed tomography (CT), magnetic resonance imaging (MRI), and bone scans are important in the assessment of advanced disease, but they are not indicated in the standard workup of low risk prostate cancer because of their low sensitivity and high cost. Physicians should adopt a symptom-directed approach to the use of imaging of low risk disease. Patients with high risk disease are more likely to have benefit from routine imaging, and many physicians use CT of the abdomen and bone scan as adjuncts to clinical staging in this group. Imaging in these patients may help to identify those with lymph node involvement, but sensitivity is poor even in this risk group. It has been suggested that MRI of the prostate can be used to categorize risk further in intermediate risk tumors by identifying seminal vesicle involvement and extraprostatic extension before surgery. Additionally, MRI is a possible adjunct for patients considering active surveillance to help rule out larger tumors that may have been missed in the initial prostate biopsy. Current imaging studies (CT, MRI, or positron emission tomography [PET] scan) cannot accurately show metastatic disease in most patients with newly diagnosed prostate cancer.
C. Pelvic lymphadenectomy. Pelvic lymphadenopathy is rarely performed in isolation in current practice. It can be safely omitted at the time of surgical therapy in patients with low risk of lymph node spread (PSA <10, Gleason 6, and T1c cancer). In an occasional patient with high risk disease, laparoscopic pelvic lymphadenectomy should be considered to rule out metastatic disease before definitive therapy. However, most of these high risk patients will receive either surgical resection or multimodality therapy with radiation and androgen deprivation.
D. Staging. The first purpose of a staging system is to provide a well-accepted classification where health care workers from around the world may interpret the extent of disease of the patient. However, in addition, the clinical and/or pathologic stage of the prostate cancer patient may guide discussions about the optimal modality for treatment. The clinical or pathologic stage of the patient is the stage that is defined at the time of initial diagnosis.
To answer queries from patients about prognosis and treatment options, one must weigh the clinical and/or pathologic tumor, node, metastasis (TNM) staging, Gleason grade, and serum PSA level in the context of the general health of the patient. The oncologist should give estimates of both prostate cancer–specific survival and overall survival. The median age at diagnosis for U.S. men is declining, but is still approximately 68 years, and the average man lives to 75 years at this time. In the future, men will get diagnosed earlier and will live longer, leading to more treatment, more “cures,” more PSA relapses, and longer times with side effects from therapies for recurrent disease.
1. Prostate cancer is staged according to the AJCC Cancer Staging Manual 7th edition. T stage is divided into T1 (clinically undetectable tumor by palpation or imaging), T2 (tumor confined to the prostate; T2a—one-half or less of a lobe, T2b—more than one-half of one lobe, T2c—bilateral lobe involvement), T3 (Extension through the prostate capsule; T3a—extracapsular extension; T3b—seminal vesicle invasion), and T4 (invasion of adjacent structures such as rectum, levator muscles, and pelvic wall). N1 is defined as the involvement of regional lymph nodes and M1 as metastases to non-regional lymph nodes, bones, or other sites. In addition to the TNM status, both PSA (<10, ≥10 to <20, ≥20) and Gleason score (G1 ≤6, G2 7, G3 >7) are used in the final staging. Stage I is defined by the presence of T1–T2a plus G1. Stage IIA is defined by T1–T2b plus PSA <20 and Gleason ≤7, and stage IIB is defined as T2c or T1–T2 with PSA >20 or Gleason score >7. Stage III is defined by the presence of T3 and stage IV by the presence of T3 and T4, N1 or M1.
2. Histologic grade
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