A commentary from Lewis S. Blevins Jr. M.D. – One of my patients asked me to review the results of a published study. The individual had learned of the manuscript on social media. The article, “Prospective intraoperative and histologic evaluation of cavernous sinus medial wall invasion by pituitary adenomas and its implications for acromegaly remission outcomes”, was published by Mohyeldin and others from Stanford University in Scientific Reports.
In the manuscript, the authors report on their findings related to evaluating medial cavernous sinus wall invasion in various subtypes of pituitary adenomas. They report their findings and focus on their results in acromegaly.
First things first, the medial wall of the cavernous sinus is made up of a tough membrane called the dura mater. I’ll spare you the complexities of the anatomy of this structure. It is, however, a reflection of the tough outer layer of the meninges that lines the inside of the skull. It forms the side boundaries of the sella. There is one cavernous sinus on each side. It separates the pituitary from the area that contains veins, nerves controlling eye movement, and the carotid artery that supplies blood to the brain on each side. It is not uncommon for pituitary tumors to invade, or grow into, the cavernous sinuses. In many patients, the tumor invading this area cannot be fully resected, leading to residual tumor that often needs to be treated depending on patient needs. Patients with hormone-secreting tumors are usually treated with one or more medications if they have an invasive residual tumor. Radiation therapy may also be required and may control tumor growth and, ultimately, hormone secretion. Nonfunctional tumors are often treated after surgery if there is significant residual tumor mass or later if they are small and progress during a follow-up period.
Traditionally, surgeons have been reticent to enter the cavernous sinuses in an attempt to resect tumors due to the risks of complications of injury to the nerves controlling eye movement, venous bleeding, and carotid artery injury that can lead to stroke and even death. In modern times, however, experienced surgeons have learned that they can identify cavernous sinus invasion during surgery with a reasonable degree of certainty and then “enter” the region to resect the tumor when there is a reasonable chance that most or all of the tumor can be resected. This is, in essence, what this particular paper is all about. I commend the investigators for their work. I do, however, have several criticisms of and comments regarding the manuscript and the approach to treatment. Please read the paper and take my criticisms with a grain of salt or as thoughtful commentary designed to inform and educate. That choice is entirely up to you, the reader, the patient who may be particularly interested in the approaches described in the manuscript.
I want to preface the next parts of this review by stating, to disclose a conflict of interest, that the physicians at Stanford are, in essence, colleagues who do the same thing that we do at The California Center for Pituitary Disorders at The University of California, San Francisco. Therefore, my commentary reflects my thoughts and opinions on the paper for our readers at Pituitary World News.
My overall opinion on advances in surgical or medical treatments is that they should be relevant, medically necessary, of a reasonable risk-benefit ratio, and likely to achieve the desired outcome. Unfortunately, I don’t think these conditions are met in some patient subsets. For example, their study included patients with nonfunctional and null cell adenomas. In my opinion, there is no reason to even think of removing the cavernous sinus wall and then entering the sinus to completely resect these lesions. Even though they did not report any serious injuries, I feel this approach was cavalier in these patients and unnecessarily put them at risk for little benefit when other treatment alternatives exist to control these residual tumors (i.e., gamma knife radiosurgery). I also believe the risks were unnecessary in those patients with lactotroph adenomas (prolactinomas), where medical therapy can control residual tumors or radiotherapy can be used to control tumor growth but is not as effective in lowering prolactin levels.
Let’s talk about the risks in more detail. The authors reported a few patients with transient cranial nerve palsies, which is, basically, a temporary loss of or diminished function of the nerves controlling eye movement. There is a real risk that such injury could be permanent. It is not uncommon with apoplexy and can happen with surgery in this region. They did not report any carotid artery injuries. There is, however, the possibility of a significant risk of injury to the carotid arteries when operating in the cavernous sinuses. It has been reported in 1 to 3% of pituitary surgical procedures. Deaths have also been reported by surgeons performing pituitary operations who inadvertently damaged the carotid artery while attempting to remove a tumor and, in some cases, while even attempting to enter the sella. The authors reported the procedure on 107 patients, of which only 50 had their medial cavernous sinus walls resected. What if they had done a lot more cases? How many patients would have had serious injuries to the carotid artery? Are 50 cases enough to claim the procedure is safe? I think not. Most published papers reflecting on the operative morbidity of pituitary surgery suggest that vascular complication rates decline after several hundred cases have been accomplished. This applies to all pituitary cases performed by the operating surgeon, but I suspect the case numbers also apply to advances in technique, too, as there is always a “learning curve” to proposed new ways of accomplishing things surgically. What if less experienced surgeons than the excellent group at Stanford decide to follow or emulate this approach given the reported findings? There would surely be deaths due to vascular injury and a few patients with permanent double vision. I was disappointed the authors chose not to report their complications regarding loss of pituitary function, hyponatremia, and diabetes insipidus. They stated it was not part of the study and glossed over the issue indicating that there were no new cases of hypopituitarism. Yet, I suspect the data are indeed available. I believe the authors have a duty to report the full spectrum of complications of the procedure, especially since the manuscript has found its way into patient arenas.
The authors report that they resected the medial wall when it appeared, via direct inspection with the endoscope, that there was cavernous sinus invasion. Pathology showed they were correct 78% of the time. In other words, 22% of patients didn’t need the added procedure. Is this proportion acceptable given the risks involved? Perhaps it is in select patients. Maybe some of those thought to have invasion actually had a surgical injury to the cavernous sinus wall. How can one distinguish injury from invasion? Which patients really stand to benefit from attempts at resection in this blood-rich compartment? When is it truly justifiable to manipulate the carotid artery in these patients?
Growth hormone-secreting tumors proved to be more invasive than other tumor types. This is in keeping with our experience and the experience of others. I would suggest, however, that the results be taken with caution as they only evaluated the medial cavernous sinus wall adjacent to the tumor. What about other areas in contact with the tumors? Normal pituitary? The clivus? Diaphragm sellae (roof of the pituitary made of dura mater)? Tumors can invade in any direction. The remnants are often microscopic. A good surgeon knows how to limit or reduce the likelihood of persistence of these small amounts of tumor. My point is that cavernous sinus invasion is not the whole story. What if a patient has an invasion of the cavernous sinus, undergoes resection of the wall, yet has a residual tumor of the diaphragm sellae and has persistent acromegaly needing radiotherapy? Would it have been wise to have resected the cavernous sinus wall in the first place? What if the tumor in the cavernous sinus couldn’t be resected and the patient still needed radiosurgery and medical therapy? Is there a decision analysis that would predict cavernous sinus wall resection failure and preclude the added procedure in some patients?
The authors reported operating on 24 patients with acromegaly over a 2.5-year period or about ten patients per year. They performed medial cavernous sinus wall resection in 81% of patients based on suspicion of invasion, but the invasion was present in only 69% of these patients. They reported remission in 92% of patients following surgery and implied that resection of the medial wall of the cavernous sinus in acromegaly patients resulted in the highest potential for biochemical remission ever reported. While I don’t entirely disagree with their number, the problem I have with the statement is that their results are not directly comparable to other studies that were larger and had longer periods of follow-up; the follow-up in this particular study ranged from just 3 to 30 months and averaged only 15.6 months. Most who treat large numbers of patients with acromegaly would likely agree that “the results are not yet in” on remission rates. Further, I’d like to learn of their results performing cavernous sinus resections in prolactinoma patients as another example of the procedure’s success.
I’m unsure why the authors choose not to publish their manuscript in a mainstream Neurosurgery or Endocrinology journal. On the other hand, I’m not sure the small size of the patient population and the absence of long-term follow-up would meet the requirements or the scientific rigor required to lead to acceptance by the well-known major journals in the disciplines mentioned. Furthermore, I feel that, in addition to proving scientific certainty of outcomes, the authors would have to elaborate more on the risks of pituitary injury and better define the risk-to-benefit ratio of the added procedure, given there are less risky alternatives to treat those with eventual residual or recurrent disease.
I look forward to seeing further studies and long-term follow-up of the findings in this patient cohort at Stanford. I’m confident they will share advances in their knowledge and understanding of medial cavernous sinus wall resection, its indications, risks, benefits, and recommendations based on experiences.
I feel that to truly understand the benefits of the surgical procedure, it might be best to do a randomized controlled study in which patients who have direct endoscopic evidence suggesting cavernous sinus invasion are randomized to either receive a traditional surgical procedure designed to remove as much tumor as is possible, or medial cavernous sinus wall resection and removal of as much tumor as is possible. Patients with residual disease should be treated with conventional measures, such as gamma knife radiosurgery and medical therapy. Only after long-term follow-up would we be able to see the true benefits and risks of this procedure compared to traditional endoscopic or microscopic endonasal nasal surgery for acromegaly. Further, one might be able to develop a decision tree analysis to determine which patients should undergo cavernous sinus wall resection with aggressive attempts at tumor removal. This approach to science is needed to determine if this procedural modification in the resection of pituitary adenomas is worthwhile in a subset of patients.
Lewis S Blevins Jr. M.D. is the Medical Director of the California Center for Pituitary Disorders at UCSF, Professor of Clinical Medicine and Clinical Neurological Surgery, and Pituitary World News co-founder.
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