Olfactory mucosa tumors: Another complication of stem cell treatments

I’ve often said in my writings that I have yet to encounter a for-profit stem cell clinic that is not a predatory quack clinic selling unproven treatments for serious diseases at high prices. Although I’ve been writing about this phenomenon and how these clinics continue to operate for quite a long time now, my interest was particularly piqued when a hometown hero, Gordie Howe, went to Mexico for an infusion of stem cells to treat his serious stroke. As a result, even though he was hardly ever shown, he became a de facto celebrity pitch man for Stemedica Cell Technologies, the San Diego company that made the stem cell product that he received at the Mexican clinic and had provided it to Howe at no cost other than his travel. Never mind that there was no good evidence that the stem cell infusion improved Howe’s neurologic function. More recently, William Shatner touted an “anti-aging” stem cell infusion that he had undergone. Meanwhile, there have been reports of spinal cord tumors as a result of dubious stem cell treatments. As the FDA tries to crack down on the most egregious offenders selling stem cell quackery, there comes another reminder that, contrary to what stem cell entrepreneurs tell us, these treatments are not without risk—in some cases, significant risk, in the form of a case report from Newfoundland in Canada of a man with a cervical spine mass after a stem cell treatment. The mass turned out to be an olfactory mucosa stem cell tumor.

Here’s the case history:

A 38-year-old man was referred to the neurosurgical clinic with a 3- to 4-year history of deteriorating neurologic function in his arms (sensory disturbance with some subjective weakness) and gradual loss of bladder function. The patient’s medical history included a C5/C6 fracture-dislocation secondary to trauma at 20 years of age. Despite having had posterior spinal fusion and rehabilitation, he had partial paralysis of his arms, and severe paralysis of his legs and trunk. According to the American Spinal Injury Association (ASIA) Impairment Scale (AIS) (https://asia-spinalinjury.org/wp-content/uploads/2019/04/ASIA-ISCOS-IntlWorksheet_2019.pdf), which grades impairment after spinal cord injury from A (complete motor and sensory deficits) to E (neurologically intact), he had sustained an ASIA D injury (i.e., motor incomplete). This means that half or more of the key muscles below the neurologic level of injury were active against gravitational resistance. At 26 years of age, the patient had undergone experimental stem cell transplantation. Using a nasal approach, the surgical team harvested an olfactory mucosa graft that was transplanted to his spinal cord lesion on the next day. Although the patient could not provide an operative report, the surgical team (Lima and colleagues) published their transplantation and surgical procedure.1 Fusion hardware was removed and he again underwent rehabilitation. Although he hoped to walk again and have resolution of his chronic pain, he never regained clinically significant motor function, and he experienced additional pain.

This is, of course, a horrific injury. This man had very severe neurologic deficits and was, in essence, a quadriplegic. Now, here’s the interesting thing. This procedure appears not to have been performed at a for-profit quack stem cell clinic. Rather, it was performed in Portugal at Hospital de Egas Moniz in Lisbon and the clinical trial protocol approved by the hospital’s ethics committee and published by Carlos Lima

I was intrigued by the procedure; so I looked up the clinical trial protocol. The timeline fits, because the operations for the clinical trial were carried out between 2001 and 2003. The trial itself enrolled seven patients ranging from 18 to 32 years of age with spinal cord injury (four men and three women). All had suffered serious spinal cord injury with paralysis, and all injuries had resulted from motor vehicle collisions save one, which had resulted from a fall.

The authors described the rationale for using olfactory mucosa grafts:

There are several potential advantages of olfactory mucosa transplants. The olfactory mucosa is a structural unit with embryonic features that offer the possibility of promoting regeneration and reconstruction. Removing part of the olfactory mucosa does not permanently damage olfaction because it is a continuously regenerating system. By using the olfactory mucosa to fill the spinal cord cavity with solid tissue as opposed to using cell suspensions, there is decreased risk of individual cells entering the cerebrospinal fluid (CSF) circulation. In an experimental transplant study, tissue (as opposed to cell suspensions derived from that tissue) was more effective and showed greater cell viability (12). During the period of adaptation to the new environment, cells may be supported by their original surrounding cell types. Olfactory mucosa transplants avoid the artificial environment of tissue culture, which also reduces the risks of the procedure. Instead, olfactory mucosa grafts preserve the CSF environment, because CSF also bathes the olfactory mucosa through the olfactory route of CSF drainage (13). The autologous olfactory mucosa graft would not be an additional burden to the immune system, because the grafted material was previously exposed to the contemporary immunological state of the central nervous system.

In addition, it is known that the two cell types in the olfactory mucosa known to be useful in the repair of the nervous system are stem-like progenitor cells and olfactory ensheathing cells (OECs). The stem-like progenitor cells divide rapidly and can develop into neurons or supporting cells. There are also a number of promising animal studies that suggest that these cells can contribute to the repair of damaged neurons. As a result, it was thought that there was sufficient preclinical evidence to do a pilot study.

The surgical procedure itself involved multiple teams and three steps. The first step involved neurosurgeons exposing the damaged spinal cord and removing as much scar tissue as possible to expose the gross viable nervous tissue in both stumps of the severed cord. This wound was temporarily closed, and then the otolaryngologists went into action to harvest the olfactory mucosa graft. Finally, the graft was implanted into the site of injury. The graft was immersed in saline or cerebrospinal fluid and cut into small pieces, after which the graft was placed at the site of injury. Patients were transferred to the surgical intensive care unit.

Six months after transplantation, MRI showed filling of the defect in the spinal cord in all patients but one, with no evidence of tumor overgrowth. There was some improvement in every patient, but reading the report, I couldn’t see the results as anything more than mildly promising and worth following up, which the same team of investigators did in a prospective, uncontrolled pilot study of olfactory mucosal autograft implantation in 20 patients who had sustained traumatic spinal cord injury 18 to 189 months previously (mean 49 months). The AIS scores improved in 11 of 20 patients and declined only in 1 patient.

However, as promising as these results might sound, we must be cautious, as the authors of the case report of the spinal mass suggest:

Studies involving transplantation using olfactory mucosal autografts notably carry several limitations. To date, patient enrollment is small, making the generalizability of results difficult. The studies are neither randomized nor blinded. The relative contributions of intensive postoperative rehabilitation and olfactory mucosa transplantation to recovery are unclear given the lack of large control groups. Some studies with questionable rehabilitation intensity and compliance showed no postoperative improvement in ASIA motor score. Although these studies claim that olfactory mucosal autograft transplantation is feasible and safe given the few adverse events encountered, their follow-up periods are limited.

Now, at a followup of around 17 years, this patient presented with a cervical spine mass, as seen on this MRI:

Olfactory mucosa stem cell tumor

The mass is best seen in A as an irregular area against the vertebral bones. Don’t worry if you can’t read the MRI; I included it for those who can. The mass extends from the C4 to C7 vertebrae. You don’t need to be able to read MRIs to see the the mass in this surgical photo from the exploration and resection of the mass:

Olfactory mucosa stem cell tumor

The suction catheter shows very thin mucinous material that was expressed from the mass (white arrow). Solid components were adherent to and infiltrating the spinal cord, resulting in the surgeons not being able resect the entire mass. So they did a subtotal resection. This is what pathology found:

Pathologic examination of the samples found mucinous material and tissue consistent with ectopic olfactory mucosa. The sections showed tissue and small cysts lined by a pseudostratified columnar epithelium (Figure 3A). Nerve twigs and submucosa glands were seen in the underlying connective tissue, with 1 slide showing bone. Results from examination of tissue using immunohistochemistry showed neurofilaments and S100 proteins within the nerve twigs, and perineurial cells that were positive for epithelial membrane antigen and glial fibrillary acidic protein positivity in some areas, likely representing gliotic spinal tissue (Figure 3B).

Translation: This was a mass with mucus in it and tissue consistent with olfactory mucosa and thus deriving from the olfactory mucosa graft. The prognosis after surgery is basically unknown. The authors report:

Between discharge and follow-up at 6 weeks, the patient became severely deconditioned because of admissions to hospital for urinary tract infection and acute pancreatitis. His injury remained classified as ASIA D, but a physical examination found either stability or slight loss of power in the myotomes of his arms and legs. Given the subtotal resection of the mass, radiotherapy was offered after consultation with colleagues in other centres in Canada to try to sterilize any residual cells in the hope of slowing regrowth of the mass. The benefit of radiation in this setting is unknown; however, further surgical resection was not possible, and there was no role for chemotherapy. Treatment with radiotherapy and rehabilitation and surveillance are ongoing.

In other words, if the radiation doesn’t work and the mass recurs, options will be very limited. Nor is this the only case of a mass following an olfactory bulb mucosa graft for spinal cord injury. The authors review several other cases of mass lesions following olfactory mucosal autografting in the medical literature, one who underwent surgery by the same medical team as the patient in this case report. Two other cases involving patients who developed similar spinal masses 5 and 7 years after autologous olfactory mucosa transplantation have been reported.

One thing that should be noted is that these patients underwent stem cell grafting procedures at a public hospital under an ethics panel-approved clinical trial protocol, and they suffered serious complications in the form of masses growing where their grafts were implanted and causing more damage to the spinal cord. Given the gap of many years between surgery and growth of the mass to the point where it caused symptoms, it’s quite possible that additional masses will be detected. Even so, I saw an additional red flag that might not have been picked up on in reports of these cases. The man in the case report I discussed is a Canadian citizen, and the woman who also developed a mass after this procedure is an American:

At a hospital in Portugal, the unnamed woman, a US citizen, had tissue containing olfactory stem cells taken from her nose and implanted in her spine. The hope was that these cells would develop into neural cells and help repair the nerve damage to the woman’s spine. The treatment did not work – far from it. Last year the woman, then 28, underwent surgery because of worsening pain at the implant site. The surgeons removed a 3-centimetre-long growth, which was found to be mainly nasal tissue, as well as bits of bone and tiny nerve branches that had not connected with the spinal nerves. The growth wasn’t cancerous, but it was secreting a “thick copious mucus-like material”, which is probably why it was pressing painfully on her spine, says Brian Dlouhy at the University of Iowa Hospitals and Clinics in Iowa City, the neurosurgeon who removed the growth. The results of the surgery have now been published.

OK, so reputable public hospital or not, this is stem cell tourism. Now, putting it together, there are two additional observations that got my skeptical antennae twitching. Her’s the first one, from the Canadian case report:

Olfactory mucosal autograft surgery costs about $50 000; with patients facing additional expenses for travel, accommodations, caregiver support and recuperation, this price can easily double. The subsequent cost for managing any complications in Canada can be the same because these patients require ongoing multidisciplinary care.

This got me thinking: Did the patients pay for the surgery? It seems rather likely that the foreign participants in this clinical trial, at the very least, paid for their surgery. Hmmm.

Now here’s the second observation, from a New Scientist story about the woman who developed a mass on her spine after this procedure:

was unable to reach the Lisbon team members, but Jean Peduzzi-Nelson, a stem cell researcher at Wayne State University in Detroit, Michigan, who advised the team on their surgical technique – she had previously tested it on rodents – claims the clinic has given the therapy to about 140 people in total. Peduzzi-Nelson adds that most of the recipients of the nasal tissue who received the right kind of rehabilitation after their surgery experienced improvement. “I am saddened to learn of this adverse event, however, the incidence of this problem is less than 1 per cent,” she says. “Many patients receiving this treatment have had remarkable recovery.”

New Scientist

My first reaction was: “Less than one percent”? That’s quite a lot, actually, given the potential morbidity and even mortality when this complication occurs. Partial paralysis could easily become complete paralysis, and pain can become unbearable.

They have? Or should I say: They had? After all, the above article is five years old. Funny, but the Canadian researchers who just published the case report I discussed did a literature review, and they didn’t mention any later studies encompassing hundreds of patients. So I hit PubMed. Nope, nothing more to see there. The last clinical trial by Carlos Lima involving olfactory mucosal autografts dates back to 2010 and was the pilot trial of 20 patients. Peduzzi-Nelson appears to have suggested that Lima’s group has done way more than 20 olfactory mucosa autografts than just 27 (the seven from the first pilot study and the 20 from the second). Which is true? Has Lima only done 27 under his clinical trial protocols, or has he gone beyond that and continued to treat patients? Does he charge for the procedure? You see where I’m going with this? Is he becoming, for all intents and purposes, no different than the for-profit stem cell clinics I regularly castigate for their unethical practices? If he is continuing to do the procedure, why hasn’t he published further about it in nine years? Is the hospital charging patients the $50,000 or more for the procedure, even though it is, by any stretch of the imagination,

I definitely smell something fishy here.

Leaving that aside, though, the most important thing to remember from this case report, the author’s conclusion:

Given the vulnerability of patients who are chronically ill, especially those with spinal cord injury or neurologic disorders who may be targets of Internet-based marketing for stem cell therapy), physicians in Canada should be aware of the rationale behind stem cell therapy as well as the reported adverse events. Both family physicians and specialists may need to counsel patients on stem cell transplantation or diagnose complications in those who have had these procedures.

Precisely. Even under the auspices of a properly designed clinical trial approved by an institutional review board, there is the potential for serious adverse reactions from stem cells. Now just imagine what could happen as a result of the unregulated sale of unproven stem cell therapies.

ADDENDUM: I just discovered that Carlos Lima died in 2012, although apparently his work still goes on. His group also claimed to have done over 120 of these procedures.