Digital cases
Case 56 (HPC:56) : Atypical neurofibroma in neurofibromatosis type 1 (NF1)
Case 105 (HPC:105) : Plexiform neurofibroma in neurofibromatosis type 1 (NF1)
UI: - Neurofibroma
Definition: A neurofibroma is a benign nerve sheath tumor in the peripheral nervous system, consisting of a mixture of cell types including Schwann cells, perineurial-like cells and fibroblasts.
Neurofibromas are benign tumors and the tumor cells have features of Schwann cells, perineural cells, and fibroblast. There are three major types of neurofibromas: cutaneous, subcutaneous, and plexiform.
Sporadic neurofibroma is a tumor of the periphery of the peripheral nervous system and occurs most commonly in the extremities. In contrast, neurofibromas in NF1 patients have an increased tendency to occur near the spinal cord and the brain and in uncommon locations such as the tongue and parotid glands.
Usually found in individuals with neurofibromatosis type 1 (NF1), a genetically-inherited disease, they can result in a range of symptoms from physical disfiguration and pain to cognitive disability.
Neurofibromas arise from Schwann cells that exhibit biallelic inactivation of the NF1 gene that codes for the protein neurofibromin. This protein is responsible for regulating the RAS-mediated cell growth pathway.
In contrast to schwannomas, another type of tumor arising from Schwann cells, neurofibromas incorporate many additional types of cells and structural elements in addition to Schwann cells, making it difficult to identify and understand all the mechanisms through which they originate and develop.
Synopsis
combined proliferation of all elements of a peripheral nerve: axons, Schwann’s cells
usually predominant cellular element: fibroblasts
markedly elongated nuclei with:
wavy serpentine configuration
rich network of collagen fibers:
may be prominent mucinous changes:
may result in mistaken diagnosis of myxoma or myxoid liposarcoma
often numerous mast cells
sometimes distorted organoid structures resembling Wagner–Meissner or Pacini’s corpuscles
+/- scattered large hyperchromatic nuclei (neurofibroma with atypia)
mitotic activity scanty or absent -MIB-1 index very low
may also be increased cellularity
+/- melanin (pigmented neurofibroma): +/- skeletal muscle differentiation (neuromuscular hamartoma) +/- granular cells similar to those of granular cell tumor +/- dendritic cell morphology and contain pseudorosettes
Suspect malignant transformation if:
- frequent mitoses
- overly expressed cell proliferation markers
- p53 in many tumor cells
Ultrastructure
enclose axons in plasmalemmal invaginations (mesaxons)
Subtypes
Neurofibromas have been subdivided into two broad categories: dermal and plexiform. The dermal neurofibromas are associated with a single peripheral nerve, while plexiform neurofibromas are associated with multiple nerve bundles. According to the World Health Organization classification system, dermal and plexiform neurofibromas are grade I tumors.
localized neurofibroma (sporadic neurofibroma)
diffuse neurofibroma
plexiform neurofibroma
epithelioid neurofibroma
Localized neurofibroma
- 90% sporadic, 10% in the setting of neurofibromatosis 1 (NF1)
- most develop between 20-30 years
- in a major nerve :
- fusiform expansion
- confined by the epineurium
- in a small nerve :
- extension in soft tissues
- circumscribed but not encapsulated
- histology :
- interlacing bundles of cells with ovoid-to-spindle, often curved, nuclei
- collagen fibres and myxoid matrix
- roppey collagen bundles
Plexiform neurofibroma
- pathognomonic of neurofibromatosis 1 (NF1)
- develop during early childhood
- affects large segments of a nerve (aspect of a bag of worms)
- histology :
- tortuous enlargement of nerve branches
- expansion of the endoneurium by myxoid matrix
- possible nuclear atypia
- malignant transformation : MPNST
Diffuse neurofibroma
- children and young adults
- 10% arise in the setting of neurofibromatosis 1 (NF1)
- ill-defined infiltration of subcutaneous tissue
- matrix of fine fibrillary collagen
- rather fusiform of rounded Schwann cells
- clusters of Meissner body-like structures
Differential diagnosis
schwannoma
malignant peripheral nerve sheath tumor
dermatofibrosarcoma protuberans
low-grade fibromyxoid sarcoma
Cytogenetics
unbalanced t(2;19) (15262441)
unbalanced t(2;16) (15262441)
Molecular biology
- NF1 chromosomal microdeletion (16830335)
- mitotic recombination (16830335)
- chromosome loss with reduplication (16830335)
Neurofibromas arise from Schwann cells that are homozygous for the inactive version of the NF1 gene. It leads to a complete loss of expression of neurofibromin.
Links
References
De Raedt T, Maertens O, Chmara M, Brems H, Heyns I, Sciot R, Majounie E, Upadhyaya M, De Schepper S, Speleman F, Messiaen L, Vermeesch JR, Legius E. Somatic loss of wild type NF1 allele in neurofibromas: Comparison of NF1 microdeletion and non-microdeletion patients. Genes Chromosomes Cancer. 2006 Oct;45(10):893-904. PMID: 16830335
