Diagnosing Extraprostatic Extension (EPE)

Extraprostatic Extension (EPE) or "Stage T3a" means the cancer has eaten through the edge of the prostate and is penetrating into the tissue outside. It can be difficult to diagnose before a prostatectomy. Sometimes, it can be felt using a digital rectal exam (DRE) as a bulge or irregular texture, but that is an exception rather than the rule. More often, it is seen on an mpMRI or ultrasound image.

It is important because its presence is a strong predictor of recurrence after treatment. It is one of three risk factors used in the NCCN definition of "high-risk" prostate cancer. That definition is based on the AJCC staging criteria (see this link), which means that it is strictly only based on DRE. DREs almost always fail to detect EPE. If the bulge is so big that one can feel it through the rectum, it adds significantly to the risk. But how much does it add to the predicted risk if it can only be seen on a powerful MRI?

Reisaeter et al. evaluated the Mehralivand EPE Grading System and found it was somewhat more sensitive in clinical practice as the commonly used Likert EPE scoring system. (The interested patient may also wish to read this editorial by Peter Choyke)

The Likert score looks at certain imaging abnormalities (tumor contact length with the prostate capsule, irregularity, bulging, gross extension, and loss of rectoprostatic angle) and summarizes them using five categories:

• 1 = criterion not present
• 2 = probably not present
• 3 = uncertain if present
• 4 = probably present
• 5 = definitely present.

The Mehralivand System uses three grades:

• Grade 1 refers to tumors with a contact length of 1.5 cm or greater or contour bulge or irregularity. 
• Grade 2 refers to tumors with a contact length of 1.5 cm or greater and contour bulge or irregularity, 
• Grade 3 refers to gross visible extension beyond the prostate.

Both systems require very well-trained radiologists - interobserver agreement is only fair.

Mehralivand compared the predictions of the EPE detection system to what was actually detected after the same patients had prostatectomies. Even when the Mehralivand System assigned Grade 3 to a suspected EPE, a third of them were false (positive predictive value (PPV) = 66%). False positives may be caused by inflammation, tumor scar tissue, or biopsy scar tissue. Contact with the capsule may be wholly inside, and a bulge may be wholly contained within the capsule. 

What's worse, the Mehralivand System incorrectly predicted there would be no EPE in 18% of cases where EPE was eventually found (negative predictive value (NPV) = 82%). False negatives are caused by tumors below the size where MRI can detect them. 

• The PPV was 41%, 48%, and 66% for Grade 1, 2, and 3, respectively
• The NPV was 90%, 88% and 82% for Grade 1, 2, and 3, respectively

Since DREs are so bad at detecting EPE, and MRIs are little better, what can be done to better predict EPE, and is better prediction necessary?

Is better prediction always necessary?

It has been found that focal EPE (extensions of less than 3 mm) and EPE comprising low Gleason score tumor tissue are not predictive of treatment failure. In this Johns Hopkins study, 10 year biochemical recurrence-free survival was 76% among men with focal EPE (post-prostatectomy) and 59% among those with more extensive EPE. A surgeon discovering a focal EPE may simply cut wider to get it all. GS 6 tumors have low metastatic potential (see this link). However, a patient who learns in advance that the surgeon will "cut wide" thereby increasing his risk of incontinence or impotence may opt instead for radiotherapy.

mpMRI-targeted transprostatic biopsy

It may be possible to detect clinically significant EPE by detecting suspicious sites using an mpMRI and following up with a real-time ultrasound fusion-targeted biopsy. Some pathologists have argued that needle-biopsy cores that show close proximity to the prostate margin, admixture with skeletal muscle at the apex, or admixture with adipose or other peri-prostatic soft tissue predict for EPE. This suggests that clinically significant EPE may be diagnosed with transprostatic needle-biopsy cores. This is an unusual procedure. Of course, as with any needle biopsy, it may miss the site, and several cores from the suspicious site should be taken. A periprostatic nerve block is required (which imho should be required on all needle biopsies) to prevent any additional pain. There is also some risk of extra bleeding if a blood vessel is nicked. It is worth discussing with the biopsy urologist. It is also important that the designated cores be evaluated by an experienced pathologist like Jonathan Epstein at Johns Hopkins.

(update June 2022) Moroianu et al. reported a "deep learning" algorithm that is better at detecting EPE from an mpMRI than a radiologist.

• Model sensitivity was 80% vs. 50% for radiologists (model predicted more true positives)
• Model specificity was 28% vs. 77% for radiologists (model predicted more false positives)

A combined computational/radiologist approach may be best.

Can invasive procedures spread prostate cancer?

Prostate cancer is seldom spread by invasive procedures such as biopsies, prostatectomy, TURP, LDR brachytherapy, HDR brachytherapy, or insertion of fiducials for image-guided radiotherapy. We know this because those procedures have high cure rates. Nevertheless, there have been isolated case reports of such inadvertent cancer dissemination occurring.

Mechanism of unintended cancer dissemination

Two direct mechanisms have been proposed as ways in which invasive procedures may facilitate the spread of cancers:

(1) by direct implantation from invasive instruments like biopsy needles or surgical knives, and

(2) by release of tumor cells into the bloodstream or lymph.

It is likely that only a few, less prevalent types of prostate cancer cells are amenable to spreading by invasive procedures. The most prevalent types of prostate cancer are incapable of survival outside of the prostatic environment. Several studies have now shown that true Gleason 6 tumors have never been known to metastasize. However, that does not preclude their eating into adjoining tissue, or possibly evolving to higher Gleason grade. Only cells that have some major alterations in their genetic structure are capable of moving through and beyond the prostate. Cancer stem cells spread readily yet are not always detected.

Detection

Until very recently, we lacked the technology to detect the very small foci of cancer cells that may have been accidentally seeded. Those foci have been found only when they grew much larger. That has occurred as long as 19 years later in one case, and then suspicion was raised because it recurred in such an unusual spot (the perineum). The advent of multiparametric MRIs has enabled us to see much smaller foci of recurrences than we have before, with the potential to see foci as small as 4 mm in length (Barchetti and Panebianco). The limit of detection may be even lower for the new generation of PSMA-antibody-based radiotracers coupled with the new PET/MRI scanners. Even so, if the cancer is in a more usual place, such as the anastomosis, how do we distinguish a cancer placed by instrumentation from one that grew there naturally?

Circulating tumor cells may be found with CellSearch® or ADNA® tests.

Biopsy

Biopsies can break off rogue cancer cells and plant them along the needle tract. This has been observed in breast cancer, liver cancer, and rarely in other cancer biopsies as well (Shyamala et al.) Although the cells are planted there, they do not remain viable for long outside of their host environment (Loughran et al.) and usually do not produce tumors. There have been isolated cases of tumors produced by needle-tracking of prostate cancer biopsies. In 1987, Haddad and Somain found 15 such cases of prostate tumors that had to have arisen following transperineal biopsies.

In 1991, Bastacky, Walsh and Epstein at Johns Hopkins found that tumor growth along the needle track was evident in the periprostatic soft tissue in 2% of the prostatectomy specimens they examined. Unlike earlier reports that only found needle tracking in transperineal biopsies of high-grade tumors, they found it in transrectal biopsies of Gleason 7 tumors as well. A recent literature review by Volanis et al. found 42 case reports of needle-tract seeding.

Another way that biopsies can potentially spread cancer is by release of isolated cells into systemic circulation. Tumor cells are less sticky than healthy cells, so they may be more easily dislodged by invasive procedures. In a recent study by Ladjevardi et al., the researchers looked at the peripheral blood (from their arms) of 38 men (23 patients with PC, 15 patients without PC) before and after prostate biopsy. They examined the blood for presence of epithelial cells that might have become dislodged by the biopsy. They found cellular material in 83% of the men who had PC, but only in 13% of the men who did not have PC. This does not mean that the epithelial cells were tumor cells, or if there were, that they were viable. The most viable kinds of tumor cells are mesenchymal rather than epithelial, but those were not searched for. It would be interesting to see this experiment repeated with CellSearch® or ADNA® technology, which can detect and distinguish circulating tumor cells.

Surgery

Some cancers are easily spread through inoculation by surgical instruments. For this reason, surgeons try to avoid cutting into the tumor. With unifocal tumors (e.g., breast cancer) the surgeon cuts a margin around the tumor. But with prostate cancer, where tumors are almost always multifocal and can be anywhere in the prostate, surgeons try to remove the entire prostate in one piece. Sometimes, surgeons slice through the tumor at the margin, leaving behind a positive surgical margin (PSM). Sometimes this is inevitable, but experienced surgeons typically have a lower PSM rate. At Johns Hopkins, for example, the PSM rate is as low as about 10%. The cancer left behind may continue to grow, may become non-viable after detachment, or may get cleaned up by the immune system. It is unknown at this time whether tumor cells detached by the cut at the PSM seed new tumors.

A similar effect may occur when an attempt is made to spare neurovascular bundles. In a study of 9,915 patients treated at Memorial Sloan Kettering and Ottawa Hospital from 1985-2010, 6% had prostate incision. Those who had bilateral nerve-sparing had incision rates over twice as high as those who did not have nerve-sparing surgery, after adjustment for confounders. Patients who had robotic surgery had incision rates almost twice as high as those who had open or laparoscopic surgery. Risk of prostate incision has decreased over time, presumably with surgeon’s experience.

Another difficulty arises where the surgeon must detach the prostate from the urethra, which runs right down the middle. The surgeon scrapes prostate tissue away from the urethra, and cuts it as far away as he can from the bladder neck on top, and the urethral sphincter, on the bottom. He then joins the two ends together, which is called an anastomosis. This procedure may leave cancerous tissue behind. In a recent CT/MRI study of post-prostatectomy tissue, 76% of recurrences after surgery were found to occur at the anastomosis. How many of those were from cancerous tissue that was left behind, and how many from contamination of the surgical blade?

Sometimes, especially with laparoscopic procedures on large prostates, the surgeon is forced to cut the prostate up into smaller pieces that he can remove through the port – a process known as morcellation. This may be especially risky for releasing cancer cells into systemic circulation. In April 2014, the FDA discouraged the use of morcellation on the uterus or uterine fibroid tumors because of the high risk of cancer spread associated with the process. Sometimes surgeons will recommend hormone therapy to their patients with especially large prostates in order to perform robotic surgery without morcellation. To my knowledge, there have been no studies of the effect of morcellation on prostate cancer spreading.

Spread of cancer at the laparoscopic port site is exceedingly rare. A 2004 study looked at 10,912 urologic laparoscopic procedures across 50 different treatment centers, and found only 10 cases of port seeding and 3 cases of peritoneal spread from the procedure. There have been only a handful of cases reported since then. Robotic laparoscopic surgery is responsible for only 3 documented cases of port site and/or peritoneal spread: one case in Japan, one case in Korea, and one case in Turkey.

Cancer cells may be released into systemic circulation by surgery. A study of circulating epithelial tumor cells in breast cancer patients found that the serum-detected cell numbers did increase in some patients following surgery, and the increase was sustained in some, indicating viability. A study of bladder cancer circulating tumor cells using CellSearch® found an increase following transurethral bladder resection. Eschwège et al. found increased numbers of prostate epithelial cells in the serum after surgery, but found no association with metastatic progression or survival. To my knowledge, there has not yet been a study specifically of circulating tumor cells pre- and post-prostatectomy.

There is not enough documented proof that the magnitude of cancer spread by surgery is large enough to be of concern. However, the potential for cancer spreading by poor surgical technique is one more reason to find the most experienced surgeon possible.

Low Dose Rate (LDR) Brachytherapy or “Seeds”

Implanting seeds is a highly invasive procedure, with 70 or more radioactive seeds injected into the prostate. In a Japanese study among 616 consecutive patients receiving LDR brachytherapy between 2003-2010, 5 patients had a pulmonary metastasis after clinical recurrence. Pulmonary metastases are rare, but they were hormone-responsive, which suggests a prostate cancer origin. The authors note that they may have been caused by seed migration to the lungs. All of those 5 had high Gleason scores, and only one had neoadjuvant hormone therapy.

High Dose Rate (HDR) Brachytherapy

Raleigh et al. at UCSF recently reported the first case of prostate cancer seeding following HDR brachytherapy treatment for a man with high risk PC treated with a combination of HDR brachytherapy and EBRT. The cancer recurred at the site where an HDR brachytherapy catheter was known to have touched the patient's bladder. The authors conclude:

"This case is the first report of prostate cancer recurrence in the bladder wall after brachytherapy and raises questions about prostate cancer biology, brachytherapy technique, and the timing of brachytherapy boost relative to whole pelvic radiotherapy for prostate cancer."
 

I hope that readers will not be dissuaded by these reports from seeking diagnostics and therapies they may be considering. There are risks with any invasive procedure, but it is important to keep the relative magnitude of those risks in perspective. I think these case studies are useful insofar as they are generative of hypotheses. It is clearly an area ripe for further scientific inquiry.