A Collaboration that Began in the Operating Room Could Revolutionize the Treatment of Skull Base Tumors

One of the first endoscopic intracranial skull base surgeries performed on a Children's Hospital of Philadelphia (CHOP) patient occurred in 2012. The undertaking was the result of a collaboration between CHOP and Penn Medicine. The patient was anesthetized at CHOP, then moved through a tunnel to the neighboring Hospital of the University of Pennsylvania (HUP).

"We did that because we had all the equipment, nursing, and experience," says James N. Palmer, MD, Director of the Division of Rhinology and Co-Director of the Cranial Base Center for Penn Medicine's Department of Otorhinolaryngology – Head and Neck Surgery.

Also in the operating room that day were Nithin D. Adappa, MD, Surgical Director of the Penn AERD Center, Director of Penn's Rhinology and Skull Base Fellowship, and Director of Otorhinolaryngology at the Perelman Center for Advanced Medicine; John Y. K. Lee, MD, MSCE, Medical Director of Penn's Gamma Knife Center and Clinical Director of its Center for Precision Surgery; and Phillip B. "Jay" Storm, MD, Chief of CHOP's Division of Neurosurgery and Co-Director of its Neuroscience Center.

Penn Medicine's Otorhinolaryngology and Neurosurgery departments, and Dr. Palmer specifically, are pioneers in endoscopic skull base surgery. They began using it to treat adult patients nearly 20 years ago. By 2010, they had established themselves among the field's leading experts. And so, it was Dr. Palmer whom Dr. Storm approached when he suggested adapting the procedure to treat CHOP's patients.

"Simply put, we took the practices we developed and the lessons we learned from adult endoscopic intracranial skull base surgery and applied them to CHOP's pediatric patients," Dr. Palmer says.

The same protocol was followed the next time the procedure was done on a CHOP patient, only this time CHOP nurses observed. The third time, all the equipment was moved to an operating room at CHOP, and the CHOP nurses participated as nurses from Penn looked on, ready to provide guidance if it was needed.

In the years since, Dr. Storm and the endoscopic skull base team have done the surgery to treat several midline skull base lesions, including encephaloceles, chordomas, sellar and suprasellar tumors, and the occasional skull base trauma. Craniopharyngiomas, a rare, benign brain tumor that usually forms near the pituitary gland and the hypothalamus, comprise the majority of his cases.

"The goal of endoscopic intracranial skull base surgery is to minimize or avoid brain retraction, manipulation of the carotid, anterior cerebral and basilar arteries, the optic nerves, and, in some instances, to avoid injuring the pituitary gland and stalk," Dr. Storm says. "A lot of the lesions arise from the skull base and push on the suprasellar arteries and nerves. If you try to remove the pathology through a craniotomy, you must do a lot of brain retraction, and the surgeon manipulates stretched nerves and arteries to access the lesion and not injure those important structures. By contrast, if you employ an endonasal technique to access the skull base lesion you can often address the pathology immediately without having to manipulate any of those structures."

Since he began doing the surgery on his pediatric patients, there have been no instances of pseudoaneurysms, where a locally contained hematoma arises because blood leaks from the injured arterial wall. Prior to 2012, pseudoaneurysms occurred in about 30 percent of the craniopharyngiomas Dr. Storm treated with a craniotomy.

Similarly, there have been only two cases of hydrocephalus, the abnormal buildup of fluid deep within the brain, with endoscopic skull base surgery for craniopharyngiomas, and no cases of hydrocephalus for all other pathologies treated with endoscopic endonasal surgery. Dr. Storm says it was a common complication of craniotomies, especially in very young children.

Strokes and ischemic events have also decreased, he says.

The student becomes the teacher

The first pediatric endoscopic skull base surgery that brought together Drs. Palmer, Adappa, Lee, and Storm in 2012 became the catalyst for a collaboration that could dramatically reshape the treatment of skull base tumors in adults and children alike within the next few years.

The Penn surgeons perfected the procedure with adult patients, then worked with Dr. Storm to adapt it to pediatric patients. Their research has worked the other way around.

"While we were busy teaching him how to do endoscopic removal of these tumors, he taught us how to bank tumors," Dr. Palmer says of Dr. Storm.

By 2012, Dr. Storm had developed a robust collection of tumors he'd removed. Each one has now undergone whole-genome sequencing in an effort to determine better means of treating them and, potentially, developing cures for the diseases that caused them. Using Dr. Storm's template, Penn began its own adult skull base tumor bank that year.

Two years later, Penn started contributing to the Cole-Reagins Sinonasal Database, or Corsica, as it became known. "They were trying to collect data on adult patients to find out what happens to them when they get skull base tumors," Dr. Palmer says. "We have so few patients with skull base tumors spread out so far across institutions, we weren't even sure what the best treatments were."

In time, and at Dr. Storm's suggestion, the seven institutions participating in Corsica, along with three others, began sending all of their skull base tumors to the Center for Data Driven Discovery in Biomedicine (D³b) at CHOP, which was founded in 2016 by Dr. Storm and Adam Resnick, PhD. The tumors are collected across Corsica using uniform standard operating procedures. The goal, Dr. Storm says, is to begin sequencing the cohort in the next year.

The 'precision medicine warehouse' is growing

Before the streamlined process that exists today, Drs. Storm, Palmer, and Adappa were simply trying to get their heads around the basic science of the first pediatric craniopharyngiomas they'd removed when they became aware that researchers at Harvard were sequencing adult craniopharyngiomas.

"It was natural for our two groups to work together, comparing and contrasting what we were finding," Dr. Palmer says.

Drs. Storm, Palmer, and Adappa discovered the adult craniopharyngiomas had a BRAF mutation (V600E), the exact same mutation that's in melanoma and in pediatric brain tumors called low-grade gliomas. "But when we looked at the craniopharyngiomas of children, not a single one had that mutation, which we thought was a little strange since they're so similar," Dr. Storm says. "But then, because we had a large number of craniopharyngiomas in our biorepository we were able obtain an NIH grant that allowed us to layer DNA, RNA, and protein data from craniopharyngiomas to find potential targets. When we looked at the protein levels, we found that all the craniopharyngiomas clustered exactly with our low-grade gliomas with the V600E mutations."

In other words, pediatric craniopharyngiomas act like another type of tumor called a low-grade glioma. Some low-grade gliomas are responding well to BRAF inhibitors. Prior to their discovery, craniopharyngiomas could only be treated with surgery and radiation. Both surgery and radiation carry significant and unavoidable morbidity in all patients, but there were no other options.

Before the end of this year, Dr. Storm expects to embark on a clinical trial that will evaluate the efficacy of a panRAF inhibitor that blocks the MAP kinase pathway where BRAF plays an important role. Their research also suggests that pediatric craniopharyngiomas may be vulnerable to a type of immunotherapy called check point inhibitors.

"We don't know if this trial will work," Dr. Storm says. "But if it does, it's going to revolutionize this disease."

And it may be just the gateway. By pooling data from Penn's adult patients and CHOP's pediatric patients, Dr. Storm expects to continue to find commonalities among their skull base tumors, which would spur new therapies and encourage reconsideration of other unlikely ones. "It's really a way to break down silos and better integrate pediatrics and adults across the whole lifespan," he says.

By continuing to collect tissue, multi-omics data treatments will become far more precise, if not outright individualized. This, Dr. Storm says, could happen within the next five to 10 years. "Because with every patient that now enters our system," he says, "that increases our precision medicine warehouse."