Neurofibroma overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2], Shanshan Cen, M.D. [3]
Overview
Neurofibromas are benign nerve sheath tumors of neural origin in peripheral nervous system, comprising all elements of the peripheral nerve (i.e. axons, Schwann cells and fibroblasts) and can occur anywhere in the body. Neurofibromas may occur as part of the syndrome of neurofibromatosis (most common), solitary neurofibromas, or multiple neurofibromas without von Recklinghausen's disease (NF-1). Neurofibroma may be classified into further subtypes such as localized, cutaneous, subcutaneous, intraneural, intramuscular, diffuse, pigmented, and plexiform neurofibroma. However, plexiform neurofibroma can be further subclassified into diffuse, and nodular plexiform neurofibroma. Gene involved in the pathogenesis of plexiform neurofibroma is NF1 which codes for neurofibromin that leads to loss of RAS control causing increased activity of downstream RAS pathways involved in increased cell growth and survival. On gross pathology, a non-encapsulated superficial mass is the characteristic finding of localized or diffuse neurofibroma; whereas the "bag of worms" appearance is the characteristic finding of plexiform neurofibroma. On microscopic histopathological analysis, nerve fibers, schwann cells, spindle cells with wavy nuclei without pleomorphism, shredded carrot collagen, moderate increase of cellularity vis-a-vis normal dermis, blood vessels, mast cells, pseudomeissnerian bodies, and varying degrees of myxoid degeneration are characteristic findings of neurofibroma. However, plexiform neurofibroma shows a characteristic target sign on histopathology. It usually affects both men and women equally between the age of 20-40 years. Common symptoms of neurofibroma include soft masses, transient itching, and transient pain with rest of the symptoms depending upon the involved site. There is no single diagnostic study of choice for neurofibroma, instead, it is diagnosed on the basis of medical history, physical examination, and imaging studies such as CT or MRI. The predominant therapy for neurofibroma is surgical resection. Adjunctive chemotherapy and medications such as ACE inhibitors may be required. Prognosis of neurofibroma is generally excellent. If left untreated, 10% of patients with plexiform neurofibromas may progress to develop malignant peripheral nerve sheath tumor (MPNST). Local recurrence occurs rarely.
Historical Perspective
NF1-like cutaneous tumor syndromes appeared in the literature in 1880s, when Friedrich von Recklinghausen published seminal observations detailing cutaneous tumors comprised of both neuronal and fibroblastic tissue finally termed as neurofibromas. In 2006, Yang et al demonstrated a critical neurofibroma microenvironment interaction that includes SCF-stimulated Nf1+/− mast cells potentiating Nf1+/− fibroblast functions.
Classification
Neurofibroma may be classified into 5 subtypes: cutaneous/dermal/localized, localized intraneural, subcutaneous, diffuse, intramuscular, plexiform and pigmented neurofibroma. Plexiform neurofibromas may be further sub-classified into diffuse and nodular plexiform.
Pathophysiology
Neurofibromas arise from the nonmyelinating-type Schwann cells. Gene involved in the pathogenesis of plexiform neurofibroma is NF1 which codes for neurofibromin that leads to loss of RAS control causing increased activity of downstream RAS pathways involved in increased cell growth and survival. Neurofibromas can occur anywhere in body. On gross pathology, a nonencapsulated superficial mass is the characteristic finding of localised or diffuseneurofibroma; whereas the "bag of worms" appearance is the characteristic finding of plexiform neurofibroma. On microscopic histopathological analysis, nerve fibers, schwann cells, spindle cells with wavy nuclei without pleomorphism, shredded carrot collagen, moderate increase of cellularity vis-a-vis normal dermis, blood vessels, mast cells, pseudomeissnerian bodies, and varying degrees of myxoid degeneration are characteristic findings of neurofibroma. However, plexiform neurofibroma shows a characteristic target sign on histopathology, representing a central core of collagenous and fibrillary tissue with peripheral less denselycellular myxoid tissue. Electron microscopy of neurofibromas shows Schwann cells enclosing axons in plasmalemmal invaginations (mesaxons).
Causes
Plexiform neurofibroma may be caused by the bi-allelic inactivation of the neurofibromatosis type I tumor suppressor gene.
Differential Diagnosis
Neurofibroma must be differentiated from schwannoma, dermatofibrosarcoma protuberans (DFSP), ganglioneuroma, dermal neurotized melanocytic nevus, myxoid liposarcoma, solitary circumscribed neuroma, traumatic neuroma, superficial angiomyxoma, nerve sheath myxoma, malignant peripheral nerve sheath tumor, spindle cell lipoma, leiomyoma, inflammatory myofibroblastic tumor, and fibroepithelial polyp.
Epidemiology and Demographics
Neurofibroma usually occurs between 20-40 years of age, and affects men and women equally. However, plexiform neurofibromas are thought to be congenital defects, hence, they occur earlier in life.
Risk Factors
Neurofibromatosis 1 and Neurofibromatosis 2 are the most common risk factors for development of neurofibromas.
Screening
According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for neurofibroma.
Natural History, Complications and Prognosis
Prognosis of neurofibroma is generally excellent. If left untreated, 10% of patients with plexiform neurofibromas may progress to develop malignant peripheral nerve sheath tumor (MPNST). Local recurrence occurs rarely.
Diagnosis
Diagnostic Study of Choice
There is no single diagnostic study of choice for neurofibroma, instead, it is diagnosed on the basis of medical history, physical examination, and imaging studiessuch as CT or MRI.
Staging
There is no established system for the staging of neurofibroma.
History and symptoms
Neurofibromas can form anywhere in body with diffuse neurofibromas commonly involving scalp. Symptoms of neurofibroma include soft masses/bumps (internal or superficial) , transient itching, pain, numbness and tingling in the affected area, severe bleeding, physical disfiguration, cognitive disability, stinging, neurological deficits, changes in movement (clumsiness in the hands, trouble walking), bowel incontinence, scoliosis, UTI, urinary retention, urgency, frequency, urinary incontinence, hematuria, hydronephrosis, or pelvic mass.
Physical Examination
Physical examination of patients with neurofibroma is usually remarkable for soft masses (internal or superficial).
Laboratory Findings
On Immunohistochemistry, neurofibroma stains positive for S100, SOX10, CD34, factor XIIIa, neurofilament, GFAP and calretinin and negative for EMA, keratin, smooth muscle actin, desmin, calponin, caldesmon and p53.
X Ray
There are no X-ray findings associated with neurofibroma.
CT Scan
CT scan may be helpful in the diagnosis of neurofibroma. Findings on CT scan suggestive of neurofibroma include a well-defined, round or oval hypodense, fusiform mass representing the nerve entering and exiting the tumor. Low attenuation is attributed to high lipid or water content within the mucinous matrix, entrapment of perineural adipose tissue and cystic degeneration.
MRI
MRI may be helpful in the diagnosis of neurofibroma. It appears as a hypointense, homogeneous low signal intensity lesion with center demonstrating a higher signal intensity than the periphery on T1. T2 weighted images show hyperintense, homogeneous lesion with positive target sign and fascicular sign. Moreover, neurofibromas have heterogeneous enhancement on T1 C+ (Gd) (with gadolinium contrast).
Ultrasound
There are no ultrasound findings associated with neurofibroma.
Other Imaging Findings
There are no other imaging findings associated with neurofibroma.
Other Diagnostic Studies
There are no other diagnostic study findings associated with neurofibroma.
Biopsy
Biopsy is helpful in the diagnosis of neurofibroma.
Treatment
Medical Therapy
The predominant therapy for neurofibroma is surgical resection. Adjunctive chemotherapy and medications such as ACE inhibitors may be required.
Surgery
Surgery is the mainstay of treatment for neurofibroma. Localized and diffuse lesions are usually treated surgically. Neurofibromas that infiltrate between nervefascicles are unable to be separated from the parent nerve, therefore, deep-seated lesions are often managed conservatively. Local recurrence after excision is uncommon .and malignant transformation occurs rarely.
Primary Prevention
There is no established method for primary prevention of neurofibroma.
Secondary Prevention
There are no secondary preventive measures available for neurofibroma.