- Teach for America, Chalmette High School, Chalmette, LA, USA
- Department of Pathology, University of California, San Francisco, CA, USA
- Department of Neurology, University of California, San Francisco, CA, USA
- Department of Neurological Surgery, University of California, San Francisco, CA, USA
Correspondence Address:
Michel Kliot
Department of Neurological Surgery, University of California, San Francisco, CA, USA
DOI:10.4103/2152-7806.120882
Copyright: © 2013 Kliot T. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Kliot T, Ince Y, Tihan T, Wilson M, Kliot M. To grow or not to grow, That is the question. Surg Neurol Int 31-Oct-2013;4:
How to cite this URL: Kliot T, Ince Y, Tihan T, Wilson M, Kliot M. To grow or not to grow, That is the question. Surg Neurol Int 31-Oct-2013;4:. Available from: http://sni.wpengine.com/surgicalint_articles/to-grow-or-not-to-grow-that-is-the-question/
Abstract
Keywords: Grow, neurofibroma, neoplasm, static, tumor
EDITORIAL COMMENTS
The following article is the first to appear in a new section of New Horizons in SNI called, “Thinking Outside the Box”. The goal of this new section is to take an interesting, but as of yet unexplained neurosurgically relevant observations with important clinical implications, and propose a plausible and testable mechanistic hypothesis. In this case, the interesting observation is that many if not most neurofibromas stop growing for long periods of time. The clinically important implication is that if we can understand the molecular mechanisms that retard or arrest neurofibroma growth, then we can: 1) convert growing tumors into non-growing or static tumors, and 2) have the option of performing a biopsy to predict which ones will likely grow and need a surgical resection, and which ones will remain static and can be observed. The mechanistic and testable hypothesis presented here is that many neurofibromas activate senescence pathways that eventually slow and even stop their growth for long periods of time. It is our hope that this section will provide a platform for physicians to voice new ideas, some of which may one day culminate in novel approaches to treat and even cure currently vexing clinical problems.
Michel Kliot, MD
INTERESTING CLINICAL OBSERVATIONS ON THE VARIABLE GROWTH OF TUMORS IN PATIENTS WITH NEUROFIBROMATOSIS-1
Neoplasms represent uncontrolled growth of cells, and usually come to clinical attention because of the symptoms and/or clinical signs they elicit. A growing number of studies examining the natural history of neoplasms show that particular types can exhibit highly variable growth patterns.[
An excellent example of variable tumor growth is exhibited by patients with Neurofibromatosis-1 (NF1). NF1 is one of the more common familial tumor syndromes with a prevalence of approximately 1 in 3500.[
Clinical experience may generate a bias in the surgeon's view of tumors since most patients who come to surgical clinics have masses that are growing and/or symptomatic. Over the past 5 years, one of the authors with a peripheral nerve clinical practice (MK) has operated on over 140 patients with peripheral nerve neoplasms that are either symptomatic and/or growing. He is also following an even greater number of patients with peripheral nerve neoplasms that are minimally symptomatic or not growing.
The mechanisms proposed in this manuscript were prompted by the observation of many examples of neurofibromas that have not grown over many years. One such patient had multiple right brachial plexus neurofibromas with highly variable growth patterns over a 3 year period, during which some tumors enlarged, some became smaller, and some stayed the same size while one neurofibroma in his thigh became malignant [
Figure 1
(a) Middle age man with multiple neurofibromas in his right and left brachial plexi showing variable patterns of growth over a 3 year period including enlargement, stasis, and reduction in size (right panel MRN done 3 years after left panel MRN). (b) A tumor in his right medial thigh developed at the later time point and is visualized on a MRN (left panel) as well as PET CT study (right panel) which showed high metabolic activity consistent with a malignant neurofibroma, a diagnosis confimed by surgical pathology
Figure 2
(a) 37 year old woman with NF1 who underwent resection of fourteen neurofibromas with variable growth patterns, 11 were tender but had not grown for several years, and three progressively grew. (b) An intraoperative image showing one neurofibroma as it is being removed. Red Arrows point to neurofibroma being removed
MOLECULAR MECHANISMS MEDIATING TUMORIGENESIS IN NF1
While it is important to recognize the neoplasms that have a propensity for progression, we believe it is equally important to understand why the overwhelming majority of neoplasms remain dormant in the setting of NF1. A few mechanistic possibilities can be proposed, and some of these are discussed briefly.
Neurofibromin down-regulates Ras, a key intracellular signaling protein for promoting cell growth and survival.[
HYPOTHESIS: THE POSSIBLE ROLE OF SENESCENT PATHWAYS IN ARRESTING THE GROWTH OF NEUROFIBROMAS
The fundamental mechanisms of the disparate growth patterns of neurofibromas in NF1 are unclear, and recent studies have pointed to a number of possible explanations especially oncogene induced senescence which is a barrier to cellular proliferation.[
CONCLUSION
Neurofibromas are both common and have extremely variable rates of growth ranging from growth arrest and even regression to slow growth or even malignant transformation with metastatic spread. All these tumor phenotypes can exist in a single patient. The important question of why most neurofibromas remain dormant for decades can lead us to the discovery of critical pathways that keep these tumors in check. Recognition of the critical importance of an intact system that favors senescence in Ras activated tumors allows us to consider a number of important points. First, such tumors are likely to escape senescence if other mutagenic events inactivate cell-cycle check points such as p16 or p53.[
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