Introduction
Neurofibromatosis type I (NF1) is an uncommon disorder that causes benign (non-cancerous) nerve tumors and skin growths. Cutaneous (skin) neurofibroma (cNF) arises from genetic mutations and is a component of NF1. cNF presents as a soft nodule under the skin at any location in the body. cNFs are benign and contain many cell types without risk of malignant transformation. However, cNF is considered a burden due to discomfort, disfiguring appearance, and psychosocial burden. Furthermore, the management of cNF is a challenge in the medical field.
What Are the Various Treatment Options for Cutaneous Fibromas?
At present, no gold-standard treatment exists for cNF. Surgical excision remains the most effective method for managing cNF. Surgical removal gives excellent cosmetic results, but general anesthesia requires trained specialists. Other challenges with surgical removal include tumor regrowth from incomplete excision, scarring, and cost burden.
The minimally invasive therapy for cNF includes physical removal by CO2 laser destruction, electrodesiccation (an electric current is used to dry the tumor), and ablation (removal of the surface layer). However, physical removal has no preventive effect on cNF, which can be improved by medicinal therapies. Non-invasive therapy of cNF involves no bleeding and maximum comfort to the patient.
Current medicinal therapies are under investigation, and none are effective and reliable. Some therapeutic options are targeting components of cNF or molecular pathways of tumor formation and maintenance. Topical medicinal therapies (applied on the surface) limit systemic (body) exposure to the medication. Furthermore, individuals with cNF may have an extensive tumor burden involvement making topical application unreasonable. The skin barrier can also prevent the penetration of the medicine. The decreased penetration can be due to the thick collagen mass present in the tumor. Systemic (oral) therapy would be ideal for the holistic treatment of cells affected by NF1 mutation.
What Are the Different Non-invasive Treatment Modalities for Cutaneous Fibromas?
To date, there is no recommended medical treatment for cNF. Still, the tested medicines are:
Topical:
-
mTOR Antagonists: mTOR is the regulator of cell growth and metabolism of cNF cells. Rapamycin (Sirolimus) is an antibiotic that inhibits mTOR. In a study, topical Rapamycin application daily for six months did not have significant systemic absorption. Everolimus, another mTOR antagonist, has also been tried for cNF treatment.
-
Immunomodulators: Imiquimod is an immunomodulator that modifies immune responses. In a study, a topical application of five percent imiquimod was performed to assess tumor volume and evaluate the inflammatory cells around the region of application. After four months, cNF showed a 15 percent reduction in tumor volume.
-
Non-Steroidal Antiinflammatory Drugs (NSAIDs): NSAIDs act against inflammation. Cells of inflammation (white blood cells) are present within cNF. NSAIDs target the proinflammatory enzymes (COX-1 and COX-2) to prevent the release of prostaglandins. Decreased inflammation through NSAIDs may be a mechanism for treatment. A study with Diclofenac injection showed that 48 percent of tumors had a partial or complete response. The primary objective was to identify inflammatory processes with tissue death while observing the associated adverse events.
Systemic:
-
Mast Cell Stabilizer: Mast cells (a type of white blood cells containing granules rich in histamine and heparin) release many signals critical to cNF development due to trauma or other triggers. Ketotifen is a mast cell stabilizer that works by blocking mast cell degranulation. In studies, Ketotifen fumarate showed a decrease in pain and itching of cNF mainly due to its antihistamine properties. However, Ketotifen is not useful for mature cNF but can prohibit the initial growing event. Side effects of the medication are mild and transient drowsiness.
-
Hormones: Hormones play a significant role in cNF development and progression. For example, women with NF1 have rapid growth in cNF size and number during puberty and pregnancy. Both progesterone receptors and estrogen are found within cNF. Various studies show that cNF cells respond by increased proliferation to hormonal (progesterone and estrogen) treatment. However, the link between hormones and cNF is evident only in a few studies. Hence, further research to identify this relationship can be beneficial. Also, excessive growth hormone (GH) secretion is noted in some NF1 patients. On the other hand, some studies have revealed an under-secretion of GH. Therefore, the exact role of hormones in NF1 is unclear.
-
Vascular Endothelial Growth Factor (VEGF Inhibitors): Research shows that VEGF (VEGF is involved in angiogenesis and new blood vessel formation) is expressed in NF1 and cNF tumors. Hence, VEGF inhibitors work against these tumors by inhibiting angiogenesis. Ranibizumab, a VEGF inhibitor, was injected into cNF in clinical trials with positive results. However, a trial targeting mTOR inhibition with Everolimus and VEGF with Bevacizumab revealed minimal changes to cNF development. The reason for the tumor's unresponsiveness to VEGF inhibitors may be the inactivity of mature cNF cells. Further, cNF cells do not rely on VEGF signaling pathways after development. Also, the trial results may not be sensitive to quantifying the changes in cNF.
Photodynamic Therapy (PDT): PDT is used to treat many skin disorders, including actinic keratosis, basal cell carcinoma, and skin T-cell lymphoma. PDT also can kill bacteria, fungi, and viruses that cause warts. A photosensitizer agent, 5-aminolevulinic acid (ALA), is a precursor to the human body’s photosensitizer (Protoporphyrin IX). When illuminated with a broadband red light source, cells succumb to death secondary to chemical tissue destruction, recruitment of inflammatory cells, and blood circulation compromise. Therefore, PDT may provide a selective treatment for cNF tumors without sacrificing surrounding normal tissue.
It is known that cNF rapidly proliferates in size early but becomes inactive in the mature stage. It is because it shuts down proliferation after reaching a certain size and remains unchanged for years. Studies should be done to characterize cNF inactivity. The targets for this attempt are the cells of origin in the early stage and tumor cells in the inactive stage. Additionally, minimizing collagen in the tumor microenvironment can prevent growth and reduce tumor size.
Conclusion
Surgical removal and destruction are the mainstays for cNFs. Future research and clinical trials are necessary to target cNF in the early stages of development. The ideal cNF therapy should prevent tumor development and progression. Medicines that target cNF biology are still under research. Future research for cellular inactivity in cNF will be essential to develop specific and effective medicinal therapy.
