Three Harvard physicians explain what this pathological finding means and what patients should consider next
For some men, what they hope will be the end of their prostate cancer story turns out to be just an early chapter: with the radical prostatectomy complete, they head home from the hospital believing they have been cured, only to learn that some cancer may have been left behind. Today, about 10% to 20% of patients who have their prostate surgically removed receive this news.
Performing a prostatectomy requires a delicate balancing act. The surgeon aims to cut out the gland and enough surrounding tissue to completely remove the cancer yet leave enough of the nerves in the surrounding tissue to preserve erectile function. To the naked eye, it can look as if all of the cancer has been removed, but when a pathologist examines tissue samples, cancer cells may be lurking right along the edge of the cut tissue. This means that some cancer cells may have been left behind, in what doctors and pathologists term a positive surgical margin.
At this point, patients’ questions abound: Does a positive margin mean that my cancer will come back? If so, when will the recurrence take place? Will it recur in the space where my prostate once was, or will it have spread to distant sites? If it does come back, what are my treatment options? To help answer these questions, editors at Harvard Health Publishing convened a roundtable discussion with three physicians from hospitals affiliated with Harvard Medical School. They talked about minimizing the likelihood of a positive margin, explained how pathologists process tissue samples, and described the use of radiation therapy, also called radiotherapy, to prevent and control recurrences. The panelists were
- Clair J. Beard, M.D., a radiation oncologist at the Dana-Farber/Brigham and Women’s Cancer Center. During her 18-year career, she has treated thousands of prostate cancer patients. She has a particular interest in how cancer treatment affects bowel and bladder function and quality of life.
- Elizabeth M. Genega, M.D., a pathologist at Beth Israel Deaconess Medical Center. An assistant professor of pathology at Harvard Medical School, she is interested in tumors of the genitourinary tract, particularly prostate, bladder, and kidney tumors.
- Andrew A. Wagner, M.D., the director of Minimally Invasive Urologic Surgery at Beth Israel Deaconess Medical Center. He is an expert in the field of minimally invasive surgery for prostate cancer, including robotic assisted laparoscopic radical prostatectomy.
Marc B. Garnick, M.D., editor in chief of Harvard’s Annual Report on Prostate Diseases and HarvardProstateKnowledge.org moderated the session.
What do you do to lessen the chances that a patient will have a positive surgical margin?
WAGNER: Most prostate cancer surgeons develop a preoperative game plan to help reduce the incidence of positive margins. We consider whether the tumor can be felt during a digital rectal exam, the Gleason score, the volume of the tumor in biopsy cores, and any preoperative MRI findings. This improves our chances of preserving the neurovascular bundles, the nerves that control erections, and the striated sphincter, which controls urinary function. But these goals can weigh against each other. Sometimes, the more nerve tissue that is spared, the greater the likelihood that the surgeon will cut into the prostate and leave cancer behind, creating a positive margin.
So, although there are no guarantees, we plan what we’re going to do ahead of time and counsel the patient appropriately. For example, if a patient has a large tumor on one side of the prostate and no cancer on the other side, we would plan to preserve nerve tissue on the side without the cancer by cutting closer to the prostate. On the side with the cancer, we’d have to cut farther away from the prostate, so there’d be no — or only partial — preservation of nerve tissue there.
Even when the disease is extraprostatic, or extracapsular, meaning that it extends beyond the prostate capsule, it doesn’t often extend more than one or two millimeters beyond the capsule [see Figure 1, below]. That often makes a partial nerve-sparing procedure an option for some patients. In this situation, I will often remove a few extra millimeters of tissue around the prostate and try to save some or most of the nerve tissue. This way, the patient might recover erectile function over time.
Figure 1: Extracapsular extension
The incidence of positive surgical margins increases in cases of extracapsular extension, which occurs when cancer cells break through the prostate capsule. To eliminate the cancer, the surgeon may need to make a wider cut around the prostate, possibly sacrificing the neurovascular bundle.
When talking about prostate anatomy, doctors may use terms like these:
anterior: toward or at the front of the body
apex: the bottom of the prostate
base: the top of the prostate
lateral: away from the center of the body and toward the sides
posterior: toward or at the back of the body.
What exactly is the prostate capsule?
GENEGA: What’s referred to as the prostate capsule is a band of fibrous tissue and smooth muscle. But it’s not a true capsule because it does not completely envelop the prostate gland, and its components intermingle with the tissue that forms the framework of the prostate. It is somewhat better delineated around the posterior and lateral surfaces of the prostate [see “Directions, please,” above], but as you move around toward the apex and anterior prostate — well, it’s generally accepted that there is no capsule at those two locations. So although we use the term capsule, it’s not a well-defined, complete structure.
How far away are the nerves from the edges of the prostate? Why are they important?
WAGNER: The entire nerve bundle is only millimeters away from the edge of the gland, or capsule. On an endorectal MRI, you can see this tract of tissue. It contains many little nerve fibers that run toward the penis, and they control erections. Depending on how close you cut to the prostate, none, some, or all of them can be spared.
During surgery, can you see anything that might make you change your preoperative plan?
WAGNER: When I’m operating, it’s unusual to see the actual tumor invading grossly beyond the capsule [see Figure 2, below], even with the magnified view we have during a laparoscopic procedure. More often the disease is inside the prostate. That’s why it’s important for us to know the various anatomic planes in and around the capsule of the prostate. The capsule is most often white; the prostate tissue inside the capsule itself is actually more tan and glandular in appearance, so I can often see a subtle change in the character of the planes of dissection during surgery. If I see such changes with magnification, I readjust and take more tissue from around the prostate to avoid cutting into the capsule and having a positive margin.
Figure 2: A cancerous prostate before surgery
The prostate sits below the bladder and just in front of the rectum. Nerves that control erections run through surrounding soft tissue. Although cancer (shown in red) may lurk at the edges of the prostate, the surgeon can’t see individual cells. Cutting too close to the prostate can leave cancer behind, creating what doctors call a positive surgical margin.
Can you feel anything that might make you think the cancer is more significant than you thought based on the biopsy?
WAGNER: During a traditional “open” procedure, surgeons rely less on visual cues and more on tactile clues from their fingers. If you feel a particularly firm area, it can suggest that the cancer is there, but it doesn’t necessarily tell you whether it extends beyond the prostate and into the neurovascular bundles. Feeling firm areas might suggest more aggressive disease, prompting you to take a little bit more tissue at the expense of the nerves.
Is a laparoscopic prostatectomy better than a robotic prostatectomy or vice versa?
WAGNER: The robotic and laparoscopic approaches are improvements over open surgery because there’s less blood loss, less pain postoperatively, and probably less scarring around the urethra. Each has advantages and disadvantages, but the reality is that the chances of having a positive margin — regardless of whether the procedure is open, laparoscopic, or robotic — are about the same, as long as it’s done by an experienced surgeon.
BEARD: That’s an important point. There’s strong evidence that, biology aside, positive margins are inversely related to the surgeon’s experience. This is particularly true after robotic prostatectomy.
What percentage of patients undergoing radical prostatectomy, whether open or laparoscopic, will end up having positive surgical margins?
WAGNER: It’s very hard to compare across hospitals. They have different pathologists, and they might judge what constitutes a positive margin differently. But the rate of positive margins at our hospital is between 10% and 15% for patients with T2 and T3 disease. And it doesn’t make a difference how the prostatectomy was performed. Whether it’s an open procedure or laparoscopic, we have found that the rates are the same.
BEARD: That’s typical. Institutional reviews of carefully selected patients reveal the risk of positive surgical margins can be as low as 10% for patients with T2 cancers and 20% to 30% for those with T3 disease. But you have to understand that these patients were carefully selected for surgery, and these data do not reflect outcomes for all T2 and T3 patients or for all surgeons. I think that when most surgeons see a bulky cancer, they suggest a different primary therapy, knowing that the chances of a positive surgical margin are high.
Assessing the tissue
How should a tissue sample be handled in order to accurately determine if there is a positive surgical margin?
GENEGA: The first thing we do is paint the external surface of the prostate with ink [see Figure 3, below]. Often we use different colors to designate the right and left sides. This is done prior to any slicing of the specimen.
There are several different standard methods to evaluate margins. One method is to take a shave margin, which is done by slicing the sample parallel to the inked tissue edge or margin to be assessed. But tissue slices can also be made perpendicular to the inked tissue edge. Exactly how the specimen will be sliced depends on the specimen we’re dealing with and the particular margin that we have to evaluate.
Figure 3: The inked edge
The black ink applied to the outside of the prostate can be seen on the edges of this whole-mount tissue slice.
Can shaving a specimen create a false positive margin, where the tumor looks like it’s at the edge of the tissue but really isn’t?
GENEGA: At a lot of institutions, pathologists will take a shave margin at the bladder neck, which links the prostate and the bladder. This technique might be more sensitive in terms of detecting a positive margin, but it also increases the potential that a “close margin,” where there’s a little cushion between the tumor and the edge of the bladder base, will be classified as a positive margin. There are advantages and disadvantages to each of the different methods; it really depends on the specimen.
What percentage of a prostate’s surface do you actually evaluate in the lab?
GENEGA: Well, it depends on how the specimen is processed. Are you going to submit the entire prostate gland for microscopic evaluation, or are you going to put in three or four sections from both the right and left lobes? When you submit the entire gland, people think you’re evaluating every aspect of the prostate, but you’re not. (You will, however, see more of the surface area than if the specimen is not submitted in its entirety.) When you slice the prostate for routine, non-whole-mount sections, each slice ranges from 2 to 3.5 millimeters in thickness, but from each of those slices, the histology lab takes slices that are only about 5 microns thick to make slides. [A human hair is 100 microns thick.] So there’s actually a relatively large surface area that you don’t see. If you were to look at the entire prostate, that would mean looking at hundreds of slides, and that’s not done.
How wide is the space between the “capsule” and the surgical margin?
GENEGA: It varies. It depends on how much tissue the surgeon decided to take based on the likelihood of extraprostatic extension. Often, the amount of soft tissue around the prostate is minimal, sometimes less than a millimeter. Therefore, in some areas, it can appear as if the ink is right at the edge of the prostate gland, so it may just be a few microns. In other areas, there might be a few millimeters between the capsule and where the surgeon cut, but probably not more than a centimeter.
Figure 4: A positive margin
This slide shows what prostate cancer looks like under the microscope. The arrow points to cancer cells touching the inked edge of the prostate, which indicates a positive margin.
What are the criteria for a positive surgical margin? Is there any correlation between the patient’s Gleason score and the likelihood of a positive surgical margin?
GENEGA: For a shave margin, which is a slice taken parallel to the true margin of the bladder neck, the inked tissue edge is irrelevant; tumor presence anywhere in the tissue of a shave margin is considered a positive margin. In contrast, to evaluate a margin as positive when the tissue has been sliced perpendicular to the inked tissue edge, the tumor has to touch the ink [see Figure 4, above]. This is how we evaluate the apex and other areas of the prostate gland.
As for any correlation, there are multiple pathologic and clinical features that are predictors of positive margins, including a high Gleason score — specifically a Gleason score greater than 7.
WAGNER: And the higher the Gleason score, the higher the risk that the patient has extraprostatic disease. This is the real crux of whether or not the patient might have a positive margin: how likely is it that the cancer is going to penetrate beyond the prostate borders into the surrounding tissue, and will the surgeon have cut far enough away from it? At the apex of the prostate where there isn’t much surrounding tissue, the tumor can go all the way up to the cut edge of the sample. So the higher the Gleason score, the greater the likelihood of aggressive, invasive cancer, which means the likelihood of positive margins is higher.
BEARD: We also consider perineural invasion, which describes cancer that tracks along or around a nerve. I know that’s controversial, and not everybody agrees that perineural invasion [PNI] correlates with either a higher Gleason score or extraprostatic disease, but our surgical data suggest that it does.
Are the nerves affected by perineural invasion the same nerves in the neurovascular bundle outside the prostate?
GENEGA: Yes. Nerves that are affected by PNI can be located outside the prostate gland or inside of it. The neurovascular bundles, which are the nerve “bands” and blood vessels that are out in the soft tissue surrounding the prostate can be involved by cancer. Smaller nerve twigs inside the prostate gland can also be affected by PNI.
What’s the significance of focal positivity?
GENEGA: In the pathology report, I’ll say that there is “margin positivity.” The urologists will then want to know the extent of the margin positivity. Is it unifocal, meaning a single positive margin or single area, or is it multifocal? That’s usually on the report, but they sometimes want to know how large the involved area is. Is it a 2-millimeter area or a large, 5-millimeter area?
WAGNER: I think it’s important for patients to know that information. A few studies have looked at the prognosis for patients who’ve had a focal, or single, positive margin versus those with multiple positive margins. I don’t think everyone agrees, but at least one published report says that the chance of recurrence is greater with multiple positive margins. An abstract of a study on this question was presented at the 2008 American Urology Association [AUA] meeting by researchers from the University of Michigan. They looked at the risk of recurrence with extensive positive margins compared with focal margins in their T2 patients — that is, patients whose cancer was confined to the prostate. They found that the patients with extensive positive margins had a 45% risk of recurrence at 10 years compared with a 15% risk of recurrence for the patients with a focal margin.
Can any of those patients be identified preoperatively?
WAGNER: Potentially. You could look at their MRI and attempt to predict outcome based on the number of positive biopsy cores and their Gleason score. But it also depends heavily on surgical technique and the degree to which nerves are spared. There are lots of different factors at play.
Does the location of the positive surgical margin make any difference?
WAGNER: Positive margins are more common at the apex, where there’s much less surrounding tissue, but they can occur in other areas, such as the bladder neck. A positive margin at the bladder neck probably has the highest likelihood of leading to biochemical recurrence, meaning that the PSA has risen to a detectable level, usually greater than 0.2 ng/ml.
Another abstract at that same AUA meeting described a study that looked at the anatomic location of the margins. The researchers found that patients with a positive margin at the bladder neck were three times more likely to have biochemical recurrence than patients with negative margins. Positive margins at the apex or laterally were equivalent in terms of recurrence, with patients twice as likely to experience biochemical recurrence as those with negative margins. That’s just one study, so I think the question is certainly open to debate.
Is the whole-mount technique any better or more accurate than the traditional way of handling prostatectomy specimens?
GENEGA: The whole-mount technique is very similar to routine processing in many ways. With both techniques, we paint the prostate gland with ink, the apex and bladder base margins are removed, and then the prostate gland is sliced, apex to base, perpendicular to the posterior surface. At that point, the whole-mount technique is different. Instead of cutting each one of those large prostate slices into multiple pieces, which would be the routine method, the individual, large slices are kept intact with the whole-mount method.
Regardless of the method, the pieces or slices of the prostate gland are then embedded in paraffin [see Figure 5, below] and processed in the histology laboratory, where slides are made for microscopic review. The routine method [see Figure 6, below] would typically yield about 50 to 60 slides. With the whole-mount method [see Figure 7, below], we typically have 10 to 15 slides to examine.
The whole-mount technique makes lovely slides that are quite useful for teaching prostate anatomy to medical residents, but I can’t truthfully say that the findings are more accurate. Some studies have shown that there’s no difference between the pathologic findings with the routine and with the whole-mount methods when the entire prostate gland is submitted for microscopic examination. But there are also studies that have shown the opposite. There are advantages and disadvantages to both techniques. Personally, I believe that it is much easier to orient each slice and to determine more precisely the location of the tumor with the whole-mount technique. I think that determination of extraprostatic extension is somewhat easier, especially when the tumors are in the anterior aspect of the prostate. And I think the determination of the percentage of tumor volume, while subjective, is somewhat easier to do with whole-mount sections.
Figure 5: Tissue in paraffin
Before slides are made, prostate tissue is preserved in blocks of paraffin wax. The top block is a routinely processed prostate sample; the bottom block is a whole-mount specimen.
Figure 6: Routine processing
Pathologists review at least four routinely processed slides to evaluate one entire slice of the prostate gland.
Figure 7: Whole-mount technique
This slide shows a whole-mount slice of a prostate gland. The cancerous areas are delineated by red dots. The letters R, L, A, and P stand for right, left, anterior (front), and posterior (back).
Obviously, the patient having a radical prostatectomy thinks it will be a curative procedure. What do you tell him when the pathology report shows positive margins?
BEARD: We tell him that his life is not at risk for the next five years, but if he wants to be disease-free between five and 10 years, his chances are best if he receives radiotherapy sooner rather than later. There are three variables that correlate with biochemical failure after prostatectomy: T3 disease, a high Gleason score, and positive surgical margins. One of the best publications on this comes from a pooled analysis of almost 2,000 patients. Patients with a positive surgical margin are one-and-a-half-times more likely to experience biochemical recurrence.
WAGNER: I agree with that. If a patient with high-risk disease comes out of surgery with a positive margin, I tell him that we’ll use all the weapons that we have at our disposal, and that we’ll take a team approach to beating the cancer. And I tell him that he’s unlikely to die from prostate cancer. Studies show that most prostate cancer patients don’t die from the disease, even if they have positive margins or extraprostatic disease.
How do you treat a patient with a positive surgical margin?
BEARD: That depends on the patient. We wait a minimum of six weeks after the prostatectomy and then ask the patient to have an MRI. We’ll determine whether his PSA is at a detectable level and review the results of the MRI. We wait at least 12 weeks after the prostatectomy to start treatment with radiation. If a patient has a simple positive margin and a reasonably good-looking tumor, and PSA was not detectable after surgery and the level isn’t rising, we might give him radiotherapy after 16 weeks, but that’s an unusual circumstance in our clinic. We tend to see high-risk patients with positive margins and Gleason scores of 8 and higher. We normally end up giving them radiotherapy combined with hormones, especially in cases of seminal vesicle involvement, persistent PSA, and broad or multiple positive margins.
Do you stratify patients based on whether their PSA falls to an undetectable level and then rises, or whether the PSA never becomes undetectable?
BEARD: Yes. It’s much more serious if your PSA never becomes undetectable. An undetectable PSA is considered 0.1 ng/ml or less.
WAGNER: If the PSA never becomes undetectable after surgery, it probably means that the disease has already spread beyond the prostate area. And that raises the question of whether the patient will really benefit from radiation. If the PSA becomes undetectable and then starts to rise, I think it’s more likely to be a local recurrence, a recurrence of cancer where the prostate used to be, especially in a patient with a positive margin. Those patients will almost certainly benefit from postoperative radiation.
Do you factor in the number of positive margins?
WAGNER: Yes, but that’s not necessarily the decision-maker. We take Gleason score into account, too.
What do you look for on the MRIs?
BEARD: We look for spots where the prostate used to be that light up or enhance when the patient is given a contrast agent. Occasionally, we’ll see an unmistakable local recurrence near the spot where the penile urethra was attached to the bladder neck during surgery. Occasionally, we’ll see prostate tissue that was left behind after surgery; that usually happens with a robotic prostatectomy and an inexperienced surgeon. The MRI also shows how much of the seminal vesicles were left behind and helps in planning treatment.
How often are the MRIs positive postoperatively?
BEARD: In our practice, they’re positive about 10% of the time.
Do you recommend MRIs in patients with positive margins after surgery, Dr. Wagner?
WAGNER: No, I don’t. I’m fairly confident that there’s not going to be residual tissue, so my approach is to check PSAs postoperatively. In a high-risk patient with a positive margin, I’ll check a postoperative PSA a little bit earlier than three months, which would be the standard time frame. If the PSA is undetectable, I’m comfortable waiting for at least six months — until the patient regains his urinary function and possibly some sexual function, assuming he was sexually active prior to surgery. Then I re-evaluate the situation. If his PSA is still undetectable but he’s at high risk for recurrence, I’ll refer him to the radiation oncology team to discuss the potential need for radiation.
Your practice sounds more conservative than Dr. Beard’s.
WAGNER: For low-risk patients, I’m more conservative. If someone has a positive margin but the tumor is confined to the prostate, or if someone has a positive margin and a limited amount of extraprostatic disease, I will wait and follow the PSA. If the PSA becomes detectable, then I’ll refer them to radiation.
When it comes to patients with positive margins and T3 disease — cancer that extends beyond the capsule or invades the seminal vesicles — I refer them to radiation relatively soon. Often they will be candidates for radiation therapy combined with hormone therapy.
BEARD: For high-risk patients, our practices really are not that different. They get combined therapy with at least six months of hormones — two months before radiotherapy, two months during radiotherapy, and two months after.
The traditional thinking has been that radiation following a prostatectomy exacerbates erectile dysfunction and incontinence. Can you comment on those issues?
BEARD: I think a lot of that goes back to the old days, when the technology didn’t deliver radiation as precisely as it does now. Now with carefully delivered IMRT [intensity-modulated radiation therapy], I see few patients who have significant complications. Studies of side effects from radiation therapy reveal that the risk of significant problems is low. People do very nicely with regard to their continence. Erectile function is a whole different story. It can take men two years to really know what’s happening with their erectile function after surgery, and we’re often treating these patients with hormones and radiotherapy during that period.
WAGNER: I agree. The reason to wait at least a few months before starting radiation is to allow the patient to regain continence; that usually takes three to six months. But after radiation, urinary incontinence is not a big problem. There can be some urinary irritation, which is usually temporary. I tell patients to expect it because the urethra and bladder receive some radiation.
As for erectile dysfunction, if they’ve had surgery and they’re going to get radiation after that, I tell them that they are likely to have permanent erectile dysfunction so they’ll be fully prepared for it.
What’s the prognosis for someone who’s had postoperative radiation due to positive surgical margins?
WAGNER: A recent retrospective study actually compared prostate cancer–specific survival in patients with positive margins who received radiation with those who hadn’t. As with some of the prospective studies that have been done, they found an increase in prostate cancer–specific survival in patients who received radiation within two years of biochemical recurrence. Even though patients had rapid PSA doubling times, they benefited from radiation. Most of them had localized disease and not metastatic disease, despite their rapid PSA doubling times. I think this study and others may change a few minds about whether patients should get early radiation.
BEARD: There are a number of studies that have looked at this question. They stratify outcomes according to several factors: Was your PSA undetectable after surgery? Was your Gleason score an 8, 9, or 10? How high was your PSA when radiation therapy started? The people with positive margins who had the best outcomes had lower Gleason scores and got radiation when their PSAs were low.
Is the radiation field different for a patient having radiotherapy after a prostatectomy versus one who opts for radiation as the primary treatment?
BEARD: Completely different. The field is based on images, and before the prostatectomy, you have the prostate to look at. When the prostate is gone, absent a mass or an area of enhancement, what you see is the bladder and bladder neck where the prostate used to be. So planning the radiation field becomes much more complicated. We look at what’s there, take measurements, and try to re-create what was cut out. We look at where the margins were positive. We can see where there’s any residual seminal vesicle. But the planning is rigorous.
WAGNER: Yes, definitely. You’ve got to worry more about the bladder, because it’s now drawn down into your field.
BEARD: I’ll allow a certain volume of the bladder to get a specific dose of radiation, and that will typically exceed what we’d normally do for a patient receiving primary radiation therapy because the bladder is right where the prostate was. So it can be really challenging to get enough radiation into the area to take care of the cancer without overdosing the bladder.
Any final comments?
GENEGA: Pathologists put a lot of effort into determining whether or not there’s a positive margin. But having a positive margin does not necessarily mean that a patient’s cancer is going to recur, even if he doesn’t have radiation therapy. Many other factors have to be considered, such as extraprostatic extension, Gleason score, and changes in PSA.
BEARD: Prostate cancer management requires a team approach. By working together across specialties, we’ve learned how to manage the surgical surprises and unexpected outcomes — and how to improve patients’ prognoses while minimizing side effects. Patients should be optimistic.
WAGNER: I agree with my colleagues. For patients with positive margins, it’s important to realize that this outcome is not a death sentence. When properly treated, most prostate cancer patients survive and lead fulfilling lives.
Originally published April 1, 2009; Last reviewed April 20, 2011