Take a look behind the scenes of a recent Case Report published in the journal CNS Oncology entitled, ‘Clinical response to pazopanib in a patient with endolymphatic sac tumor not associated with von Hippel–Lindau syndrome‘. In this peek behind the paper series, we ask first author of the study, Thomas Nelson (Cedars–Sinai Medical Center, CA, USA) about the clinical presentations of endolymphatic sac tutors (ELSTs) not associated with von Hippel–Lindau (vHL) syndrome. Thomas also discusses the current treatment options that are available for ELSTs and what further research is needed to verify the use of pazopanib.
Why did you select this case to write up in a case report?
There were a few points that we found interesting about this case, though our primary goal, given the rarity of the tumor, was to add to the existing body of literature about ELSTs. This may help other providers more readily identify these tumors as diagnostic uncertainty may lead to suboptimal treatment.
Regarding treatment, the primary modality is surgery, but due to the location and vascularity of these lesions, total resection may not be possible. In those circumstances, adjuvant therapy is not standardized and prior case series have highlighted treatment heterogeneity with disparate outcomes. We are hopeful that novel agents like pazopanib – mechanistically a multi-kinase inhibitor – may prove effective as treatments for these tumors and may afford providers and patients new therapeutic options.
What is the clinical presentation of a patient with ELST not associated with vHL syndrome?
ELSTs originate from the endolymphatic sacs or ducts of the inner ear and erode nearby structures, including into the cerebellopontine angle. The clinical presentation, often due to involvement of structures within the cerebellopontine angle, may consist of progressive hearing loss, tinnitus, vertigo, headache, imbalance or ataxia, and nausea/vomiting. In prior case series, the most common symptoms were hearing loss (>90%), tinnitus (~90%) and vertigo (~60%). Hydrocephalus and its sequelae, from compression of the fourth ventricle, may be seen as well.
There is a female preponderance with diagnosis typically occurring in the first through eighth decades of life and a median age of presentation in the fourth decade. Although there is a strong association between ELSTs and vHL syndrome, the clinical presentations of sporadic and vHL-associated disease are typically similar with regards to the ELST-specific symptomatology.
How do ELSTs that are associated with vHL syndrome differ from those that aren’t and how does this impact treatment?
vHL syndrome is a multisystem, primarily autosomal dominant cancer syndrome associated with ELSTs, CNS hemangioblastomas, retinal hemangiomas, renal cell cancer of the clear cell type, renal or pancreatic cysts, pancreatic neuroendocrine tumors, pheochromocytomas and papillary cyst adenomas of the epididymis or broad uterine ligament. ELSTs have been reported in 9–16% of cases of patients with vHL and in a prior series of patients with diagnosed ESLTs, 24% had vHL.
However, some cases of sporadic ELST have been associated with somatic mutation of the VHL tumor suppressor gene. As ELSTs, of both the sporadic and vHL-associated types, are rare, we look to trials of agents for vHL and vHL-associated tumors to guide chemotherapeutic treatment decisions. A putative mechanism for antiangiogenic agents has been proposed for tumors associated with vHL and therefore extended to ELST, with recent trials of pazopanib demonstrating objective response – assessed using RECIST criteria – of various neoplasms in patients with vHL. It is currently unclear if there are modalities or chemotherapeutics that would be more effective for sporadic ELST, such as seen in our patient, than in vHL-associated neoplasia.
What are the current treatment options available for ELSTs?
Treatment of ELST is primarily surgical, with complete resection being potentially curative. Early intervention is paramount as neurologic deficits may be permanent. Adjuvant radiotherapy is not standard of care, though it has been shown to slow or stop progression of disease in half of patients undergoing subtotal resection. The role of chemotherapeutic agents in the treatment of ELST is similarly unclear, though patients in whom a subtotal resection is performed would benefit from nonsurgical interventions. Even when ELSTs are identified early, patients may require trials of several agents before an effective regimen is established. To date, there have been no clinical trials of chemotherapeutic agents specifically targeting ELST, though response to antiangiogenic therapies in vHL may demonstrate a role for these agents in ELST.
What further research needs to be done to verify the use of pazopanib as a treatment for ELST?
The two metrics most suggestive of pazopanib as an effective treatment for ELST are longitudinal response and generalizability of the agent. Our patient demonstrated a substantial clinical and radiographic response to pazopanib despite having minimal response to bevacizumab, which one could posit should have a similar effect. It will be key to continue to monitor his progress with serial examinations and imaging to ensure this response was not limited in duration. If other patients with ELST are tried on this agent with similar effect, it would lend credence to its use.
Meanwhile, larger trials of pazopanib and other related novel chemotherapeutics, both for vHL-associated tumors and ELST, may help establish a more robust repertoire of agents for lesions that cannot be resected in toto. The tolerability and safety profile of pazopanib must be considered as well, with larger trials, such as by Jonasch et al.(2017), demonstrating grade 3–4 laboratory abnormalities and concurrent grade 1–2 symptomatic toxicities. Though not a panacea, we are optimistic about the use of pazopanib for vHL-associated neoplasms and ELSTs.
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.
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