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(Radiographics. 1999;19:185-203.)
© RSNA, 1999

ONCODIAGNOSIS PANEL

Oncodiagnosis Panel: 1997

Prostatic Carcinoma

Colleen A. Lawton, MD1, David Grignon, MD2, Jeffrey H. Newhouse, MD3, Paul F. Schellhammer, MD4 and Deborah A. Kuban, MD4

1 Departments of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 (C.A.L.)
2 Pathology, Harper Hospital, Detroit, Mich (D.G.)
3 Radiology, Columbia Presbyterian Medical Center, New York, NY (J.H.N)
4 Radiation Oncology, Eastern Virginia Medical School, Norfolk, Va (P.F.S., D.A.K.).

Index Terms: Prostate, neoplasms, 844.324 • Prostate, therapeutic radiology


   INTRODUCTION
Top
 INTRODUCTION
CASE 1
 CASE 2
 CASE 3
 CASE 4
 References
 
Adenocarcinoma of the prostate affects hundreds of thousands of American men annually. Treatment options for the disease vary widely from observation to very aggressive surgery or radiation therapy, which now is available in several forms. Much debate exists as to the best or most appropriate treatment for the various stages of this disease.

Because of the magnitude of prostate cancer as a disease entity as well as the controversy surrounding its management, prostate cancer was the featured topic of the Oncodiagnosis Panel at the 1997 scientific assembly of the Radiological Society of North America. Experts on urologic oncology (P.F.S.), radiation oncology (D.A.K.), diagnostic radiology (J.H.N.), and pathology (D.G.) were presented several cases of varying stages and types of prostate cancer for discussion. The ensuing article outlines each case as presented in the Oncodiagnosis Panel followed by questions posed to the experts and their commentaries given in response. What is clear from the discussion is that much is known about this disease but much has yet to be learned.


   CASE 1
Top
 INTRODUCTION
 CASE 1
CASE 2
 CASE 3
 CASE 4
 References
 
A 60-year-old man was found to have an elevated level (6.3 ng/mL) of prostate-specific antigen (PSA) with a screening blood test. Results of the digital rectal examination were negative. Transrectal ultrasonography (US) and US-guided biopsy were performed, and one of the six core biopsy specimens contained adenocarcinoma of the prostate classified as Gleason score 5. The patient is looking for treatment options.

Pathologist's View
Question: What Is the Gleason Scoring System Used in Adenocarcinoma of the Prostate?—The Gleason scoring system, which was first described in 1966, is based on the architectural growth patterns of prostatic adenocarcinoma (1). The histologic patterns are grouped into five grades, which are viewed as a continuum. In the original Veterans Administration studies, it was found that tumors behaved more like the "average" grade rather than the highest grade present; therefore, Gleason developed a "score" based on the grade of the predominant pattern added to the grade of the second most prevalent pattern (eg, predominant grade 4 + secondary grade 3 = score 7). In general, undergrading of prostate cancer is much more common than overgrading (2). Grouping of Gleason scores has varied, but all concur that cancers with Gleason scores 8–10 represent poorly differentiated, highly aggressive tumors. In addition, most now agree that Gleason score 7 cancers do not belong with Gleason score 5 and 6 tumors as an "intermediate" category. Gleason score 2–4 carcinomas almost exclusively originate in the transitional zone, have a low malignant potential, and are rarely found in needle biopsy specimens. Gleason score has repeatedly been shown to be a powerful prognostic factor, regardless of whether patients are treated by surgery (3) or radiation therapy (4).

Gleason grade 1 tumors consist of closely packed, uniform, round glands arranged in a nodule with pushing borders. This pattern is very uncommon except in transitional zone adenocarcinomas and is almost never seen in needle biopsy specimens. Gleason grade 2 tumors (Fig 1) are similar to grade 1 tumors, except the glands show more variability in size and shape and are separated by more abundant stroma. The tumor nodules have a less circumscribed appearance, although infiltration of benign glands is not seen. Gleason grade 3 tumors include three distinct architectural patterns, with the most common consisting of well-formed, relatively uniform glands growing in an infiltrative manner (Fig 2); growth between benign glands is a useful clue to this grade. In the second type, the glands are small with inconspicuous or even absent lumina and may have an angulated shape; however, they are still separate without fusion into cords or chains (a grade 4 pattern). The third type of grade 3 tumors includes papillary and cribriform patterns with islands of tumor cells that have smooth, rounded, pushing type edges without stromal infiltration. Gleason grade 4 tumors also have several distinct architectures, with the most common pattern consisting of small acinar structures, some with well-formed lumina, fusing into cords or chains (Fig 3): This pattern is frequently misclassified as grade 3. Grade 4 tumors also include a papillary-cribriform type, although the edges are more irregular and have an invasive appearance compared with that of the grade 3 papillary-cribriform type; many, although not all, endometrioid carcinomas fall into this category. The hypernephroid pattern, which is characterized by nests of cells with abundant clear cytoplasm and small hyperchromatic nuclei, is also a type of grade 4 tumor. Gleason grade 5 tumors have two major architectural patterns. The first type is characterized by minimal glandular differentiation and includes any carcinoma with little or no evidence of glandular differentiation: These tumors can consist of infiltrating single cells (including signet-ring cell carcinoma) to solid sheets of tumor cells. The second type also includes papillary-cribriform carcinomas with central necrosis (comedocarcinoma pattern).



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  		Figure 1. Figures 1–3 (1) Gleason grade 2 adenocarcinoma. Photomicrograph shows a tumor composed of well-formed round glands growing in a relatively circumscribed nodule. (2) Gleason grade 3 adenocarcinoma. Photomicrograph shows a tumor composed of uniform small glands that are growing in an infiltrative pattern. (3) Gleason grade 4 adenocarcinoma. Photomicrograph of a needle biopsy specimen shows the tumor growing as solid fused glands. A benign gland is seen in the center.

 


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  		Figure 2. Figures 1–3 (1) Gleason grade 2 adenocarcinoma. Photomicrograph shows a tumor composed of well-formed round glands growing in a relatively circumscribed nodule. (2) Gleason grade 3 adenocarcinoma. Photomicrograph shows a tumor composed of uniform small glands that are growing in an infiltrative pattern. (3) Gleason grade 4 adenocarcinoma. Photomicrograph of a needle biopsy specimen shows the tumor growing as solid fused glands. A benign gland is seen in the center.

 


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  		Figure 3. Figures 1–3 (1) Gleason grade 2 adenocarcinoma. Photomicrograph shows a tumor composed of well-formed round glands growing in a relatively circumscribed nodule. (2) Gleason grade 3 adenocarcinoma. Photomicrograph shows a tumor composed of uniform small glands that are growing in an infiltrative pattern. (3) Gleason grade 4 adenocarcinoma. Photomicrograph of a needle biopsy specimen shows the tumor growing as solid fused glands. A benign gland is seen in the center.

 
Diagnostic Radiologist's View
Question: What Is the Role of CT and MR Imaging in the Detection of Extracapsular Disease?—Before the advent of magnetic resonance (MR) imaging, computed tomography (CT) was seriously assessed as a tool for differentiating prostate cancer confined to the gland from extraprostatic disease (5–8). Signs such as the irregularity of the prostate margin and obliteration of the angle between the prostate and adjacent seminal vesicle were investigated. At first, these signs were believed to be relatively accurate, but, with increasing experience and the addition of MR imaging information, it became apparent that CT data were not sufficiently sensitive nor specific for the detection of extraprostatic disease to be used for therapeutic decisions.

MR imaging certainly has better contrast resolution and better spatial resolution, both because of the use of intrarectal surface coils and the ability to integrate images in multiple planes. Many series have been published that compare MR imaging results with pathologic findings, and the literature contains a number of proposed figures for sensitivity, specificity, positive- and negative-predictive values, and overall accuracy of MR imaging in the detection of local extracapsular disease (9–17). The range of these estimates, however, is relatively wide (eg, 64%–91% accuracy has been reported), and very high accuracy is precluded by (a) the frequency of microscopic regions of capsular invasion that are below even the best spatial resolution of MR imaging; (b) the wide differential diagnosis for the findings that frequently connote tumor; and (c) the inescapable technical difficulties relating to patient motion, postbiopsy changes, and other factors. As a very general rule, local staging of prostate tumor on the basis of transrectal MR imaging findings will be correct in approximately three-quarters of cases.

Other information from pretherapeutic work-up, including clinical estimates of stage based on the digital rectal examination, histologic grade, and PSA levels, also strongly affects the likelihood of extracapsular disease. Although MR imaging remains the most accurate imaging modality for local stage estimation, its relatively high cost, the competing staging information available through less expensive nonradiologic means, and its less-than-perfect accuracy have precluded its universal use in pretherapeutic work-up.

For this particular patient, the Gleason score was not high, the PSA level was relatively low, and biopsy results suggested that the tumor was of low volume. These characteristics suggest that the likelihood of extracapsular disease is small and that the possibility that cancerous cells might be found in the specimen margins (should surgery be performed) is even smaller. Under these circumstances, the chances that either CT or MR imaging findings would lead to a change in therapy are small.

Question: What Is the Role of Bone Scanning and Indium-111–labeled CYT-356 Scanning in Evaluating Early-Stage Disease?—Skeletal scintigraphy, if it demonstrates metastatic disease, drastically changes the preoperative stage and appropriate therapy and is not particularly expensive. Nevertheless, it may be waived if the likelihood of metastatic disease is sufficiently low. A number of studies have correlated the results of skeletal scintigraphy with PSA levels and have found that, with a PSA level of less than 10 ng/mL, the likelihood of positive bone scans is exceedingly low (18–27), so that the study may be omitted. In reality, even some patients with low PSA values undergo bone scanning as part of a standard work-up, and such scans, even if negative, may have value as baseline images should the patient require evaluation for metastatic disease later.

Scintigraphy performed with In-111–labeled CYT-356 can demonstrate extraprostatic disease if it is of sufficient volume (28–34). Nodal metastases may be also identified, even in cases in which the nodes are not enlarged and CT results are false negative. Still, the role of In-111–labeled CYT-356 scanning in evaluating early disease is limited: In patients with low Gleason scores and low PSA values, the likelihood of nodal disease of any degree is very low, and, since most prostatectomies are preceded by pelvic node sampling (which can reveal even very small deposits of tumor), In-111–labeled CYT-356 scanning is not in universal use. Nevertheless, it may be of value in a patient at high risk for disseminated disease because of a high PSA value or high Gleason score but without CT or MR imaging evidence of nodal enlargement and for whom demonstration of metastases would preclude radical prostatectomy. In-111–labeled CYT-356 scanning may also demonstrate skeletal metastases, but the evidence that its accuracy exceeds that of standard skeletal scintigraphy is insufficient for it to be the agent of choice. Certainly in a patient with a low PSA value, the likelihood of In-111–labeled CYT-356 scanning demonstrating a true-positive skeletal abnormality is probably very low.

Urologic Oncologist's View
Question: What Are the Treatment Options for Early-Stage Disease and How Do You Think Patient Age Affects Those Options?—Treatment options for this healthy 60-year-old man with Gleason score 5 carcinoma in one of six core biopsy specimens and a PSA value of 6.3 ng/mL must include surgery (either by the perineal or retropubic route), radiation therapy (either by external beam or interstitial delivery), expectant management or "watchful waiting," or hormonal therapy. An American Urologic Association guidelines panel reviewed the literature to evaluate the appropriateness of available treatment options and concluded that no one therapy could be categorically recommended under these circumstances. The patient would need to be informed about all treatment options and to play a strong role in the decision-making process. Perhaps more than in any other situation dealing with treatment recommendations for malignancy, in the case of prostate cancer, the physician guides but the patient decides.

The initial overwhelming enthusiasm of urologic surgeons for radical prostatectomy for all cases of localized prostate cancer has been modified, specifically for men over 65 years of age. According to the Medicare database, between 1990 and 1994, the frequency of radical prostatectomy for men over age 65 years has decreased, and this trend is seen in each subgroup, 65–69 years, 70–75 years, 75–79 years, and over 80 years (35). The role of age in the treatment selection process is illustrated by the recent Surveillance, Epidemiology, and End Results analysis, which indicates that surgery is more frequently directed to the younger man and external beam radiation therapy to the older patient (36).

For this particular individual who had a well-localized lesion, PSA value in the 4.0–10.0 ng/mL range, and Gleason score of 5—all of which indicates, according to the Partin table analysis (37), that the cancer is likely (50%–75% probability) confined to the prostate—radical prostatectomy appears to be the best option. This opinion, however, should be expressed to the patient only after he has "done his homework" and sought second opinions from other urologists and radiation oncologists. The patient should certainly not be discouraged from choosing radiation therapy, given the state-of-the-art techniques. The patient should be discouraged from choosing watchful waiting, since cancer progression over his 15–20-year life expectancy is likely; however, the patient should also be counseled that his cancer might be indolent and never progress or require therapy in his lifetime (38).

Question: At What Point Do You Recommend Laparoscopic Lymphadenectomy?—Laparoscopic lymph node dissection was introduced in the late 1980s. This procedure allowed surgical staging of lymph nodes in patients who were considering perineal prostatectomy, external beam irradiation, or transperineal interstitial brachytherapy. Because the prevalence of positive lymph nodes in patients undergoing radical retropubic prostatectomy at this time approached 25%, this staging maneuver promised to be helpful. However, with the advent of PSA screening and the increase in the number of cancer cases diagnosed at stage T1c, the prevalence of positive lymph nodes has fallen to the 2%–3% range. Obviously, the expense and morbidity of laparoscopic lymphadenectomy is not appropriate with such a low yield. To warrant this extra staging procedure, patients with a greater than 25% risk of positive lymph nodes must be identified, and algorithms that use clinical stage, biopsy results, Gleason score, and pretreatment PSA level have been developed to assess this risk.

This particular patient's likelihood of having positive lymph nodes, based on the Partin table analysis, is 1%–3% (37). Therefore, he is not an appropriate candidate for laparoscopic lymphadenectomy before perineal prostatectomy, interstitial brachytherapy, or external beam irradiation. In fact, pelvic node dissection in conjunction with radical retropubic prostatectomy may be omitted because of the low probability of positive findings.

Radiation Oncologist's View
Question: What Are the Treatment Options for Early-Stage Disease and How Do You Think Patient Age Affects Those Options?—This patient would be a good candidate for either of the current radiation therapy procedures, external beam irradiation or radioisotopic implant. The Patterns of Care in Radiation Oncology–Genitourinary Subcommittee, sponsored by the National Cancer Institute, recently considered therapeutic options for a similar case. This group of experts believed that the most acceptable treatments included prostatectomy; external irradiation, specifically to the prostate only and not encompassing seminal vesicles or lymph nodes; and interstitial implant. The combination of external beam irradiation and implant was thought to be "probably acceptable," although the external beam component may not be necessary. Antiandrogen therapy in addition to external irradiation was deemed unacceptable because of the patient's early-stage disease with good prognostic factors.

Although outcome data on similar early-stage disease categories have been published, treatment results for the stage T1c group are lacking because of the relatively recent trend to base prostate cancer diagnosis on an elevated serum PSA level instead of palpable abnormality. The Table lists several pertinent studies, the outcomes of which are quite similar, especially since different definitions of disease-free status were used (39–45). At the 1997 Consensus Conference of the American Society for Therapeutic Radiology and Oncology, outcome data for patients with stage T1c disease were compiled from six institutions. Of 151 patients with initial PSA values in the 4–10-ng/mL range, 88% showed no evidence of PSA level progression at 5 years after radiation therapy (unpublished data). Kupelian et al (45) studied patients with stage T1–T2 prostate cancer who were at low risk for treatment failure, had an initial PSA value less than 10 ng/mL, and a Gleason score less than 6. Among these patients, regardless of whether they were treated by prostatectomy or external beam irradiation, there was no significant difference in the 5-year disease-free survival rate; for both groups, the failure-free rate was 80%. Because screening has improved and because patients with prostate cancer are presenting at increasingly younger ages, the studies from Fox Chase Cancer Center (46) and Stanford University (47) have become especially pertinent. The former showed no age-dependent difference in disease-free survival at 5 years after external irradiation; specifically, patients younger than 65 years old do not have a worse outcome (46). The latter study has the advantage of long-term follow-up (out to 20 years) and showed significantly lower overall and local recurrence rates in patients aged 60 years or less (47). The cause-specific survival rates in this group were higher as well, although not statistically significant (47).


   CASE 2
Top
 INTRODUCTION
 CASE 1
 CASE 2
CASE 3
 CASE 4
 References
 
A 52-year-old man had clinical stage T2b adenocarcinoma of the prostate, a Gleason score of 8, and a PSA value of 9.1 ng/mL. Bone scintigraphy and CT of the abdomen and pelvis were performed to stage the patient's disease, and both indicated metastatic disease was not present. The patient underwent prostatectomy, and at final pathologic analysis, a Gleason score 7 tumor with extension into the right periprostatic fat but negative margins was found. Seminal vesicles and lymph nodes were also disease free. After surgery, the man's PSA value was less than 0.1 ng/mL, but 18 months later, it rose to 0.4 ng/mL. At 30 months after surgery, his PSA value was 3.1 ng/mL. Bone scintigraphy, plain radiography, CT of the abdomen and pelvis, In-111–labeled CYT-356 scanning, and MR imaging were performed to look for disease. The patient is wondering what he can do to gain control of the cancer.

Pathologist's View
Question: What Is the Pathologic Staging System for Prostate Cancer?—Clinical and pathologic staging are recognized as having major significance in predicting the biologic behavior of prostate cancer. Although a variety of staging systems have been used, the American Joint Commission on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM system has gained general acceptance (48). Limitations of clinical staging, in particular the inaccuracy in predicting the final pathologic stage, have been well recognized. The lack of a pathologic staging system (pT) based on the AJCC/UICC TNM clinical staging categories was reviewed at a recent consensus conference (49,50), which resulted in such a system being developed for the 1997 TNM system. The following discussion highlights the current issues and proposals for pathologic staging.

Stages T1a and T1b refer to prostate cancers diagnosed from transurethrally resected prostate tissue in patients who were not suspected of having prostate cancer. The distinction of stage T1a from T1b is based on an estimate of the total percentage of the surface area of the resected tissue that is involved with cancer, with stage T1a being less than or equal to 5% involvement and stage T1b being greater than 5% involvement. There are no pathologic stage equivalents in the radical prostatectomy specimen. Stage T1c refers to prostate carcinoma diagnosed from needle biopsy specimens in a heterogeneous population of patients in whom no lesions were found either at physical or transrectal US examination. Data from radical prostatectomy series have highlighted the wide range of pathologic stages represented in this group (51). The use of needle biopsy to "stage" prostate disease has been the subject of many recent reports (52,53). These studies have consistently found that some quantification of tumor amount and distribution (as well as PSA value and Gleason score) allows the final pathologic stage to be predicted. There is no pathologic equivalent to stage T1c in the radical prostatectomy specimen.

Tumors confined to the prostate gland at the time of radical prostatectomy are categorized as stage pT2. Although the concept of lobes may have some clinical utility when a lesion is evaluated at digital rectal examination, lobes are not definable at either gross or histologic examination of the resected prostate; thus, substaging prostate cancer by lobes is not practical pathologically. Multifocality of prostate cancer further complicates histologic evaluation, so further subdivision of the pT2 category is not included in the current pT system. Tumor can be present at a surgical margin without histologic evidence of tumor spread into extraprostatic tissues; such cases are best classified as stage pT2 with margin positivity rather than being assumed to be stage pT3 (50). In our experience, the failure rate for this disease category (21%) is roughly halfway between the rates for prostate-confined tumors with negative margins (8%) and for tumors with extraprostatic extension (39%).

Stage pT3 disease is defined as histologically identifiable invasion of the tumor into extraprostatic tissues. If tumor spread is limited to periprostatic fat (regardless of whether it is unilateral or bilateral), the disease is classified as stage pT3a. Variable application of terms such as capsular invasion, capsular transgression, capsular penetration, capsular effraction, extracapsular extension, and extraprostatic extension has led to confusion in the literature. The anatomy and histologic characteristics of the prostate gland further add to this difficulty, since no consistent histologic landmarks in the apical region and along the anterior surface exist to define a "capsule." Recent reports have indicated that the extent (quantity) of tumor spread into periprostatic fat is useful for subdividing the pT3a group into specifically significant subgroups with different rates of disease-free survival (54).

Stage pT3b disease is categorized as invasion of the seminal vesicles in the current TNM system. Seminal vesicle invasion is defined by extension of tumor into the muscular wall of the seminal vesicle and represents an important indicator for a poor prognosis in the evaluation of the radical prostatectomy specimen.

Finally, stage pT4 refers to gross involvement of adjacent structures (urinary bladder, rectum, pelvic side wall) by prostate carcinoma. Microscopic involvement of the bladder base margin at the time of radical prostatectomy is not considered to represent stage pT4 disease.

Involvement of the surgical resection margins is known to be an important predictor of treatment failure and reduced survival rates in patients who undergo radical prostatectomy (55). Recent reports indicate that quantification of the amount of involvement may be prognostically important; to test this parameter, a reproducible method of quantification must be determined. This issue has recently been studied by the Wayne State University group, and a substantial difference in disease progression has been found between cases with less than 8 mm of positive margin length and those with more than 8 mm (12% vs 38%) (unpublished data). The possible importance of distinguishing patterns of margin involvement as they relate to tumor biologic characteristics also needs to be explored. Categories such as surgically induced (incision of the gland) bulging positive margins and tumor extending to the limit of surgical margins have been suggested (55).

Question: How Does the Gleason Score from the Needle Biopsy Specimen Correlate with the Disease Stage after Prostatectomy?—This case also raises the issue of disagreement between Gleason scores from needle biopsy specimens and those derived from radical prostatectomy specimens (56). The observed discrepancies may arise from several sources. First, prostate cancers are well recognized for their multifocality and heterogeneity; for this reason, a needle biopsy specimen may not be representative of the entire tumor (ie, sampling error). Second, in cases in which only a limited amount of tumor is present in the biopsy specimen, it is difficult to infer the architecture, and therefore the Gleason grade, of the tumor nodule. Finally, as was noted in case 1, the Gleason scoring system is viewed as a continuum; thus, there are no absolute criteria for the transition points between grades, which introduces interpretive variability (57). The greatest discrepancies occur in cases in which low (2–4) Gleason scores are assigned to needle biopsy specimens (56). It is also not surprising, given that grade 3 is by far the most common, that tumors assigned scores of 8 or greater on the basis of biopsy specimens are often found to harbor foci of grade 3 tumor (resulting in downgrading, most often from score 8 to 7).

Diagnostic Radiologist's View
Question: What Is the Likelihood That Changes in Bone Scan Results Represent Metastatic Disease and Can CT or MR Imaging Elucidate Benign versus Malignant Changes?—In this patient, whose PSA level steadily rose from a postoperative value of less than 0.1 ng/mL to 3.1 ng/mL over a period of 21/2 years after radical prostatectomy, the chances that recurrent local or metastatic disease is present are exceedingly high, regardless of a change in bone scan results from normal to abnormal (58–61). Because scintigraphic findings did convert from negative to positive in a region particularly prone to metastatic disease from prostate cancer (62,63), it is relatively unlikely (especially in the absence of degenerative disease or trauma) that the change was due to anything but metastasis (Fig 4a). The volume of blastic change and the partial involvement of a pedicle seen at radiography and CT suggests that the diagnosis of a Schmorl node is unlikely. Many additional blastic foci, which most likely represented metastases, were also seen on other images (Fig 4b). Furthermore, the MR imaging appearance (64–68) was not consistent with findings of Schmorl nodes: Neither herniated nucleus pulposus in the center of the lesion nor adjacent disk changes were evident (Fig 4c).



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  		Figure 4a.  (a) Follow-up bone scan reveals a region of intense activity (arrow) in the lumbar spine. (b) Axial CT scan reveals blastic regions (arrow) at same location. (c) Sagittal T1-weighted MR image reveals a low-signal-intensity lesion (arrow) in the vertebral body.

 


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  		Figure 4b.  (a) Follow-up bone scan reveals a region of intense activity (arrow) in the lumbar spine. (b) Axial CT scan reveals blastic regions (arrow) at same location. (c) Sagittal T1-weighted MR image reveals a low-signal-intensity lesion (arrow) in the vertebral body.

 


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  		Figure 4c.  (a) Follow-up bone scan reveals a region of intense activity (arrow) in the lumbar spine. (b) Axial CT scan reveals blastic regions (arrow) at same location. (c) Sagittal T1-weighted MR image reveals a low-signal-intensity lesion (arrow) in the vertebral body.

 
It is intriguing that several blastic lesions seen at CT were not identified at skeletal scintigraphy; the degree to which the two examinations can be expected to reveal identical findings in blastic metastatic disease has not been thoroughly investigated. However, the failure of In-111–labeled CYT-356 scanning to demonstrate positive findings at the same sites as seen at CT does not exclude the possibility of metastasis: A volume of metastatic tumor sufficient to induce change visible at CT or scintigraphy may not be sufficient to bind a detectable amount of In-111–labeled CYT-356.

Urologist's View
Question: What Is the PSA Doubling Time and When Is It Appropriate to Refer Patients for Postoperative Irradiation for Persistent Local Disease?—The decision regarding the appropriate therapy for patients with rising PSA levels after radical prostatectomy is indeed difficult. External beam radiation therapy to the pelvic bed is a logical option, but it will be effective only if the disease is localized to the field of radiation and is radiosensitive. Too often, distant metastatic disease, either present at the time of initial surgery or emanating from persistent local disease after surgery, will negate the best efforts for controlling local disease.

One of the most useful parameters for determining whether a patient has persistent local disease ("local failure") or metastatic disease is the time interval between the surgical date and the first rise in PSA levels. A study from Johns Hopkins Medical Institutions investigated 51 patients with increasing PSA levels who did not undergo any form of therapy during the period of PSA level rise. Metastatic disease was identified when the increase in PSA values occurred within the first 12 months after surgery; local failure only, without metastatic disease, was identified in 50% of patients when the PSA level rise occurred 2 or more years after surgery (69).

In this patient, the possibility of local failure is reasonably high, based on the time elapsed before his PSA levels increased. External beam radiation therapy would, therefore, be an appropriate treatment recommendation.

Radiation Oncologist's View
Question: What Is the Best Way to Evaluate and Treat This Patient?—It is essential to know whether this young patient's recurrent disease, as evidenced by a rising PSA level, is localized or disseminated. Treatment options would be very different, depending on the extent of disease.

In this case, the patient underwent a biopsy of the L4 vertebra that revealed findings consistent with metastatic prostatic carcinoma. He subsequently began antiandrogen therapy, and his treatment plan included intravenously administered doses of strontium-89 every 3 months for three rounds, according to Amersham Healthcare Protocol Pr96MT02. If the patient had proved to have recurrent disease only in the prostatic fossa, he would have been offered local irradiation.

The latest studies indicate that patient outcome is better if therapy is applied as early as possible once the PSA level begins to rise. Schild (70) showed that 75% of patients were free from relapsed disease 5 years after radiation therapy was performed for recurrent disease after prostatectomy if their PSA levels were less than 1.1 ng/mL when therapy was initiated. If the PSA value was higher than this, only 25% of patients were disease free.


   CASE 3
Top
 INTRODUCTION
 CASE 1
 CASE 2
 CASE 3
CASE 4
 References
 
A 65-year-old man with a PSA value of 3.1 ng/mL had symptoms of urethral obstruction. Medical treatment with terazosin hydrochloride and finasteride was tried, but his symptoms failed to improve. His PSA value rose to 6.3 ng/mL, and the patient underwent a needle biopsy of the gland, which revealed a Gleason score 9 adenocarcinoma and clinical stage T3c disease. Results of bone scintigraphy and CT of the abdomen and pelvis were negative for metastases. The patient quickly developed urinary retention and underwent placement of a Foley catheter and subsequently a transurethral resection of the prostate (TURP). At pathologic analysis, a Gleason score 10 ductal adenocarcinoma was found. The patient underwent external beam irradiation to the whole pelvis (dose, 50.4 Gy), followed by a boost dose of 70.2 Gy to the prostate. Four months later, the patient experienced more symptoms of urethral obstruction, and palpable nodules were found in the penis. Cystoscopy revealed urethral masses consistent with prostate cancer, and CT of the chest, abdomen, and pelvis and bone scintigraphy showed lung, liver, and bone metastases. Antiandrogen therapy was started with a good response.

Pathologist's View
Question: What Are the Other Prostate Cancer Variants and How Can One Differentiate Them from Adenocarcinoma?—Although the variants of the usual small acinar type of prostatic adenocarcinoma are uncommon, it is important to recognize them because of the differences in patient presentation and prognosis (71). In general, these variants rarely occur in a pure form and nearly always are seen in association with the small acinar type. Almost all these tumors are aggressive and are considered to be Gleason grade 4 or 5. The more common variants include mucinous adenocarcinoma, signet-ring cell carcinoma, ductal or endometrioid adenocarcinoma, small cell carcinoma, and sarcomatoid carcinoma.

Mucinous adenocarcinoma (Fig 5) is associated with elevated PSA values, a similar pattern of metastases (including bone), and hormone sensitivity (72,73). It is histologically characterized by mucin lakes containing tumor cells, often arranged in cribriform masses or incomplete glands. The diagnosis of mucinous adenocarcinoma is restricted to cases with at least 25% of the tumor volume composed of extracellular mucin lakes; this pattern is considered to be Gleason grade 4. Primary mucinous carcinoma of the prostate must be pathologically distinguished from mucinous carcinomas of bladder and rectum, which may directly invade the prostate gland. Positive immunohistochemical staining for PSA and prostatic acid phosphatase (PAP) is useful for confirming a prostatic origin.



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  		Figure 5.  Mucinous type of prostatic adenocarcinoma. Photomicrograph shows a tumor composed of small glands and nests of cells floating in a background of extravasated mucin.

 
Signet-ring cell carcinoma frequently manifests at an advanced stage and is associated with a poor prognosis (74,75). The diagnosis is restricted to cases with at least 25% of the tumor volume consisting of signet-ring cells. The tumor cells have a cytoplasmic vacuole displacing the nucleus, which results in the typical signet-ring appearance, and characteristically diffusely permeate the prostatic stroma. This pattern is almost always associated with other patterns of poorly differentiated adenocarcinoma. However, the tumor cells stain positive for both PSA and PAP. As with the mucinous variant, primary signet-ring cell carcinoma of the prostate must be differentiated from secondary signet-ring cell carcinomas invading or metastasizing to the prostate from other sites.

Ductal or endometrioid variants of prostatic adenocarcinoma generally manifest in a manner similar to that of common prostatic adenocarcinoma, but the tumor can be exophytic into the urethra and produces a papillary lesion visible cystoscopically (Fig 6) (76,77). Patients with this variant may present earlier with hematuria or urethral obstruction, and the disease can be diagnosed with TURP specimens. These patients reportedly have lower than expected PSA levels on a stage-for-stage basis. The tumors are often, although not always, located primarily in the larger prostatic ducts in the periurethral region. They grow with a papillary or cribriform pattern and frequently contain a mixture of the two architectural types. The tumor cells are columnar with pseudostratification and show substantial nuclear anaplasia, with large nuclei having coarse chromatin, prominent nucleoli, and frequent mitoses. In general, ductal adenocarcinomas are graded as Gleason pattern (77), but comedonecrosis is common in this pattern and, when present, indicates a Gleason grade of 5 (pure tumors almost always receive a Gleason score of 8 or 9). The tumors stain positive for PSA and PAP, findings that help differentiate them from transitional cell carcinoma and secondary involvement of the prostate by colon carcinoma.



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  		Figure 6.  Ductal type of prostatic adenocarcinoma. Photomicrograph shows a tumor growing with a papillary architecture with pseudostratified, tall columnar tumor cells that have large vesicular nuclei with macronucleoli.

 
Small cell carcinoma (Fig 7) is a rare variant of prostate carcinoma that may occur de novo but more often manifests in a patient with known prostate cancer in whom the disease rapidly progresses but without the anticipated increase in PSA level (78–80). Patients usually present with advanced-stage disease, unusual metastatic patterns (eg, liver involvement), and relatively minor increases in PSA level. Rare cases with paraneoplastic syndromes, including Cushing syndrome, Eaton-Lambert syndrome, hypercalcemia, syndrome of inappropriate antidiuretic hormone, and hyperglucagonemia, have been reported. The histologic diagnostic criteria are the same as those for bronchogenic small cell carcinoma: The tumor is composed of cells with small to intermediate-sized nuclei, finely distributed chromatin, inconspicuous nucleoli, and scant cytoplasm. Nuclear molding is prominent, and there are frequent mitoses and apoptotic bodies. Over 50% of cases also have a typical acinar pattern of adenocarcinoma. Neuroendocrine markers (neuron-specific enolase, chromogranin, serotonin, calcitonin, adrenocorticotrophic hormone, bombesin, etc) are positive in many but not all cases. Stains for PSA and PAP are only occasionally positive in the small cell component but are positive in acinar areas when present. These cases require clinical correlation to exclude tumor spread from another site, particularly the urinary bladder.



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  		Figure 7.  Small cell carcinoma of the prostate. Photomicrograph shows a tumor composed of cells with small hyperchromatic nuclei that have granular chromatic and inconspicuous nucleoli. There is scant cytoplasm, and the cells do not form any glandular structures.

 
In rare cases, carcinomas of the prostate develop a malignant spindle cell component. These tumors are known by many terms; currently, most authors report them under the heading of sarcomatoid carcinoma (carcinosarcoma, metaplastic carcinoma, spindle cell carcinoma) (81–83). The tumors almost always develop in elderly patients and are associated with previous or concurrent high-grade prostate adenocarcinoma. In about 50% of cases, the patient has a history of radiation therapy for prostate cancer. The PSA level may be normal or only slightly elevated, and there is a very poor prognosis. The tumors are biphasic, with carcinomatous and sarcomatoid components. The spindle cells have marked nuclear pleomorphism and frequent mitotic figures, with the most common patterns being malignant fibrous histiocytoma–like and high-grade sarcoma of no specific type. Heterologous elements such as osteosarcoma, chondrosarcoma, and rhabdomyosarcoma can be present. The epithelial (carcinomatous) component is cytokeratin and stains positive for PSA and PAP; in the sarcomatoid elements, stains for PSA and PAP are only focally positive or absent. These tumors must be distinguished from primary sarcomas, phyllodes tumor, postoperative spindle cell nodule, and pseudosarcomatous fibromyxoid tumors.

Diagnostic Radiologist's View
Question: Although Initial Bone and CT Scans of the Abdomen and Pelvis Were Read as Negative, What Is Your Interpretation?—In this patient, the initial bone scan study was positive. This finding might be considered unusual in view of his relatively low PSA level, but the PSA value would undoubtedly have been considerably higher if the patient had not been taking finasteride and it might have been higher still if his tumor had not been so undifferentiated. The CT scans were initially read as showing no skeletal disease, but at subsequent review, changes in bone indicative of metastatic disease were seen that corresponded to the sites of increased uptake on the bone scans (Fig 8). Pelvic CT also revealed a thickened bladder wall and dilated ureters; these findings are consistent with chronic bladder outlet obstruction due to malignant or benign prostate disease but are not specific for either the presence or extent of malignancy (84).



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  		Figure 8.  Axial CT scan of the pelvis reveals a lytic bone metastasis (arrow) at a site identical to the region of radionuclide uptake seen on the bone scan.

 
CT performed 6 months after external beam radiation therapy demonstrated further metastatic disease, consisting of low-attenuation areas in the liver and nodules in the lungs (Fig 9). These findings are usually encountered only in late-stage disease but should not be surprising in this case because metastatic disease was already evident at the time of radiation therapy, because no systemic treatment was undertaken, and because the tumor was highly undifferentiated.



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  		Figure 9a.  (a) Axial CT scan obtained 6 months later reveals multiple low-attenuation hepatic lesions consistent with metastatic disease. (b) Axial CT scan of the chest shows multiple peripheral pulmonary nodules (arrows).

 


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  		Figure 9b.  (a) Axial CT scan obtained 6 months later reveals multiple low-attenuation hepatic lesions consistent with metastatic disease. (b) Axial CT scan of the chest shows multiple peripheral pulmonary nodules (arrows).

 
Urologist's View
Question: What Is the Role of Terazosin Hydrochloride and Finasteride for Symptoms of Urethral Obstruction?—The classic symptoms of prostatism are often not secondary to abnormal prostate size or physiology. Therefore, the most current terminology for what was previously called prostatism is lower urinary tract symptoms. Complaints of lower urinary tract symptoms warrant a physical examination, which includes a digital rectal examination; a urine analysis; and, in men with life expectancy greater than 10 years, measurement of the PSA level. Complaints of lower urinary tract symptoms alone do not warrant radiologic evaluation, cystoscopy, or cytologic analysis.

Treatment of urethral obstruction—in the absence of hypertension, hematuria, urinary tract infection, or palpable abnormalities that suggest malignancy—is directed entirely toward relieving symptoms and consists of medical therapy with alpha blockers (eg, terazosin hydrochloride, doxazosin mesylate, or the 5-{alpha} reductase inhibitor, finasteride) (85). Improvement of symptoms can be assessed by the American Urologists Association symptom score profile.

Some of these pharmacologic agents affect PSA level. The alpha blockers have not been shown to alter PSA level; however, 5 mg of finasteride taken daily will, after 6 months, depress the PSA level by approximately 50%. Therefore, a patient with a PSA value of 4.0 ng/mL will have a PSA value in the 2.0 ng/mL range after 6 months therapy with finasteride. Similarly, the baseline PSA value for a patient who is taking finasteride at the time of presentation is obtained by doubling the PSA level; that is, a PSA value of 3.0 ng/mL translates to a corrected baseline of 6.0 ng/mL.

Radiation Oncologist's View
Question: What Is the Role of Radiation Therapy in Locally Advanced Disease?—Because current studies of the use of irradiation alone to treat locally advanced prostatic carcinoma show substantial room for improvement, attention has now focused on combined modality therapy. Radiation Therapy Oncology Group (RTOG) studies (86,87) and one European study (88) showed that disease-free survival rates (and even overall survival rates in the latter study) were improved by adding antiandrogen therapy either before irradiation as a debulking agent (87) or following irradiation as true adjuvant therapy (87,89).

A follow-up RTOG study (86–96) has met accrual and will be preliminarily reported in the near future. This study compares a short course of hormonal therapy before radiation therapy with antiandrogen therapy both before and after irradiation. Because even high-dose conformal therapy has not markedly affected outcome of locally advanced and especially high-grade lesions (89), it seems only logical that a systematic treatment component is necessary.


   CASE 4
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 INTRODUCTION
 CASE 1
 CASE 2
 CASE 3
 CASE 4
References
 
A 63-year-old black man with a history of metastatic prostate cancer presented with substantial bone pain. Ten years before, adenocarcinoma of the prostate metastatic to bone had been diagnosed; at the time, the patient underwent TURP and orchiectomy. Three years later, he had more symptoms of urethral obstruction and underwent a second TURP, which revealed Gleason score 9 disease. Two years after the second TURP, he began a course of antiandrogen therapy because of more symptoms. Eight years after the original diagnosis, the patient's PSA level rose to 20 ng/mL, and 2 years later, his PSA level rose to 1,510 ng/mL. Because of further symptoms of urethral obstruction, the patient underwent a third TURP, which showed Gleason score 9 disease. Results of bone scintigraphy were floridly positive.

Diagnostic Radiologist's View
Question: What Are Your Thoughts about the Bone Scan Results 8 and 10 Years after Initial Diagnosis and Can Bone Scan Findings Help Predict Prognosis?—Eight years after the initial diagnosis, bone scintigraphy in this patient showed increased uptake at multiple locations in the spine and in the hips, shoulders, knees, and ribs; moderate left hydroureteronephrosis was also seen (Fig 10a). Two years later, the uptake on bone scans became more severe, and in the region of the spine, thorax, and pelvis, the increased activity approached the appearance of a "superscan" (Fig 10b). Two months later, radiography revealed multiple, widespread, ill-defined blastic changes throughout the thorax, lumbosacral spine, and ribs.



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  		Figure 10a.  (a) Image from a bone scan study (anterior view on left; posterior on right) reveals increased uptake in the spine, hips, shoulders, knees, and posterior left rib. (b) Image from another bone scan study performed 2 years later reveals more florid increased uptake in the spine, ribs, shoulders, pelvis, knees, and left femur.

 


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  		Figure 10b.  (a) Image from a bone scan study (anterior view on left; posterior on right) reveals increased uptake in the spine, hips, shoulders, knees, and posterior left rib. (b) Image from another bone scan study performed 2 years later reveals more florid increased uptake in the spine, ribs, shoulders, pelvis, knees, and left femur.

 
In addition to documenting the progression of skeletal metastatic disease, bone scintigraphy can be used to stratify risk: There is a direct relationship between the number of metastases and estimated life span (90–93).

Urologist's View
Question: What Is the Role of Multiple TURPs versus Radiation Therapy for Local Palliation of Urethral Obstruction Symptoms?—Repeated TURPs in patients with locally recurrent prostate cancer risk incontinence. Furthermore, the procedure does nothing to alter the local growth of the tumor and, therefore, prevent further obstructive symptoms and the need for another future resection. A more logical treatment would be use of radiation therapy to reduce tumor size and guard against recurrence of urethral obstruction.

Question: What Is the Appropriate Treatment for Hormone-Refractory Prostate Cancer?—It is important to be very specific in the description of metastatic disease that has failed treatment with antiandrogens (94). Such tumors have customarily been generically referred to as hormone refractory. However, these tumors include widely diverse types that should be divided into subgroups (both for assigning prognosis and treatment and for assessing response); namely, tumors that are androgen independent but possibly hormone responsive versus those that are truly hormone independent (or refractory). Androgen independence is documented by continued increase in PSA levels despite castration levels of testosterone. In this era of medical castration, there are individuals for whom the luteinizing hormone–releasing hormone agonist does not consistently achieve castration levels of testosterone. In these patients, surgical castration is appropriate to ensure testosterone or androgen independence. However, androgen independence does not necessarily mean a tumor is hormone refractory, because in a number of trials secondary hormone manipulations have achieved a response. The most common of these methods is simply antiandrogen withdrawal in patients who do not respond to combined androgen blockade (95). Furthermore, recurrence manifested by PSA progression after withdrawal of the antiandrogen flutamide may respond again to a different antiandrogen bicalutamide (96). Similarly, secondary responses after antiandrogen failure have been reported with use of ketoconazole and prednisone (97). Therefore, the definition of hormone-refractory disease requires failure of the disease to respond to at least one or perhaps two further attempts at hormonal manipulation beyond medical or surgical castration.

No prospective randomized trial has demonstrated an advantage to patient survival in the use of cytotoxic therapy after a tumor becomes hormone refractory. However, a large prospective randomized trial comparing prednisone alone to prednisone plus mitoxantrone demonstrated that the latter combination provided statistically significant palliative benefit to patients with symptomatic hormone-refractory disease (98). Phase 2 studies employing combinations of paclitaxel, estramustine phosphate sodium, and VP 16 have demonstrated promising activity as measured by a greater than 50% decrease in PSA level (99).

A number of noncytotoxic approaches include administration of differentiating agents (retinoids, vitamin D), signal transduction manipulations, and gene therapy strategies.

Radiation Oncologist's View
Question: What Impact Does Race Have on Prevalence of Prostate Cancer?—Black men have higher prevalence and mortality rates for prostate cancer than any other race or nationality in the world (100). Black Americans not only present with higher stage disease compared with white Americans, but they also have lower 5-year survival rates within each disease category, whether it be localized, regional, or metastatic. The increased mortality rate among black men is thought to be due to less screening, later diagnosis, more undifferentiated tumors, and perhaps compromised access to health care in this population (100,101).

Question: What Is the Role of Radiation Therapy in Palliating Painful Bone Metastases?—In this patient with proved metastatic disease, two methods of radiation therapy could be offered. Sr-89 could be administered intravenously to address the disseminated disease in its entirety. Acting as a calcium analog, this isotope concentrates selectively in sites of osteoblastic metastases and decays by beta particle emission with a half-life of 50.5 days. Up to 5,000 cGy may be delivered to osseous tumor deposits. Studies show relief of symptoms in the majority of patients, who then have less need for subsequent palliative radiation (102). Side effects can include an initial pain flair and decreasing blood counts, especially in patients who have received chemotherapy. The second irradiation method widely available is palliative external beam therapy delivered to particular symptomatic sites. This treatment can be expeditiously accomplished, usually in 1–2 weeks, with minimal side effects and substantial chance (70% of cases) of pain relief.


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  		Percentage of Patients Who Are Disease Free 5 Years after Treatment for Prostate Cancer
 


   Footnotes
 
Address reprint requests to C.A.L.

From the Oncodiagnosis Panel at the 1997 RSNA scientific assembly.

Abbreviations: PAP = prostatic acid phosphatase PSA = prostate-specific antigen TURP = transurethral resection of the prostate

Received for publication June 22, 1998. Revision received September 14, 1998. October 15, 1998. Accepted for publication October 16, 1998.


   References
Top
 INTRODUCTION
 CASE 1
 CASE 2
 CASE 3
 CASE 4
 References
 

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