Cutaneous neurofibroma tumors research and clinical trials

Cutaneous Neurofibromas (cNFs) are benign tumors histologically, but they significantly impact the quality of life of people with NF1 due to disfigurement, pain, itching and interference with daily activities. cNF progress in number and size from childhood through adulthood often numbering in the hundreds or thousands of tumors and are listed as the biggest concern by most people with NF1.

The cell types within a cNF are very similar to those within pNFs (NF1-/- Schwann cells, fibroblasts, inflammatory cells), but they have a very different natural history than pNF in that: (1) they effect far more people with NF1, (2) they are limited to the skin, (3) they progress across the lifespan impacting adults the most. Although the neoplastic (NF1 -/-) Schwann cell is required for cNF formation, a hallmark of cNF tumors is the infiltration of inflammatory cells (mast cells and macrophages) that can often lead to pain and itch.

Efforts are underway to comprehensively define the natural history of cNF. The “Natural History Study of Cutaneous Neurofibromas in People with NF1” is assessing cNF over time via a whole-body 3D camera (Vectra 360) in 500 people living with NF1 across all ages, skin types, and degrees of tumor burden to describe the rate of appearance of new cNFs and change of existing cNFs over a five-year interval. Another study is evaluating potential genetic modifiers that may be associated with a high versus low burden of cNF in adults with NF1 via a genome-wide association analysis (GWAS). Another GWAS study was recently conducted using data from a large French multicenter NF1 patient cohort with extensive molecular (Illumina OmniExpressExome chip) and phenotype (standardized questionnaire) characterization (manuscript in press). A final natural history study for cNF is focused on outcomes of cNF treatments in current use at NF specialty centers in Australia and France.  Collectively, these studies are filling the gaps in knowledge about the behavior of cNF before and after conventional treatments and identifying factors that influence clinical behavior of cNF.

The mainstay of current clinical management of cNFs is either “watch and wait” or destruction including surgical excision, electrodessication and laser-based therapies. Surgical resection is the most widely used approach and is often effective but associated with local healing concerns and may not be feasible for the hundreds of skin tumors people with NF1 often have. Electrosurgical excision and laser treatments are techniques that allow for treatment of hundreds of lesions in a single or a small number of sessions, but again is associated with scaring or incomplete treatment.

Three ongoing clinical trials are assessing laser, ultrasound and injection based or topical drug therapies for cNFs in people with NF1 with some early promising results. These clinical trials are using patient reported outcomes and measurement techniques developed specifically for NF1 associated cNFs. In addition, there has been recent development of multiple preclinical and ex vivo model systems to support the development and selection of therapies for cNFs.

Since 2016 NTAP has committed over $13.5 million dollars across 26 cNF projects to advance the field and support the rapid development of effective therapies that will prevent, stop or shrink cNFs. Great progress has been made and we welcome new and novel ideas to address this urgent, unmet, clinical need in adults and children with NF1.