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.

Mechanisms of unintended cancer dissemination

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

  • By direct implantation from invasive instruments like biopsy needles or surgical knives, and
  • 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 14 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 track. 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 et al. at Johns Hopkins found that tumor growth along the needle track was evident in the periprostatic soft tissue in 2 percent 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-track 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 prostate cancer; 15 patients without prostate cancer) 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 percent of the men who had prostate cancer, but only in 13 percent of the men who did not have prostate cancer. This does not mean that the epithelial cells were tumor cells, or if there were tumor cells, 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 percent. 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 Cancer Center and Ottawa Hospital between 1985 and 2010, 6 percent 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 percent 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 our 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 three 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 three 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 and 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 patients 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 prostate cancer 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.

The “New” Prostate Cancer InfoLink hopes 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. The above-mentioned case studies are useful insofar as they are generative of hypotheses. This is clearly an area ripe for further scientific inquiry.

Editorial comment: This commentary was written by Allen Edel for the “New” Prostate Cancer InfoLink.

4 Responses

  1. Fascinating. This was never discussed by three different urologists who performed biopsies and surgery on me. I am particularly interested in your statement “Several studies have now shown that true Gleason 6 tumors have never been known to metastasize”. Do you have a supporting link or reference?

  2. Archie:

    See for example this paper by Ross et al. When they went back and looked at 22 out of 14,123 cases in which a patient had positive surgical lymph nodes and was also said to have had a pathologic Gleason score of 3 + 3 = 6 or less, they found that in 19 of those 22 cases the patient really had had a higher Gleason score. (The relevant pathological specimens weren’t available for re-examination in the other three patients.)

  3. In addition to the Ross et al. study, here are a few more that confirm their findings.

    A study at NYU looked at 857 men with pathological Gleason 6 who experienced biochemical failure. All but 2 had local failures (the cancer had not metastasized) and those 2 were found to have been Gleason 7 on re-review.

    A study from the Netherlands found that among 449 surgically treated Gleason 6 patients, none had lymph node metastases, none had distant metastases, and none died after median follow-up of 100 months.

    A study from the U. of Chicago found only 36 cases out of 2,544 prostatectomies where pathology demonstrated Gleason 6 and T3 (extraprostatic extension or seminal vesicle invasion). 27 of the 35 reviewed cases were found to actually be Gleason 7s, and 3 cases were down-staged to T2. Among the remaining 5 cases, none were seminal vesicle invasions (T3b), and there was only focal extraprostatic extension (T3a). Conversely, all cases of extensive and established T3a were found to have Gleason pattern 4 at the site.

  4. Excellent review Allen. Thanks for gathering all this information in one place. This discussion raises its head periodically on the forums and your review will be a great resource.
    Here’s a link to an Inspire post addressing this issue in a less rigorous manner; I believe it covers all you have mentioned.

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