Neurofibroma, Solitary
Key Points
Neurofibromas are tumors that arise from nonmyelinated Schwann cells and perineural fibroblasts
Isolated neurofibromas are benign, slowly growing, unencapsulated neoplasms that usually arise from cutaneous nerves, with the occasional involvement of deep organs or bone nerves
As many as 90% of solitary lesions occur sporadically, but 10% are associated with neurofibromatosis type 1 or 2
The pathophysiology of both sporadic and syndromic cases of neurofibroma is similar and results from a deletion in the NF1 gene
Solitary lesions on the eyelid present as circumscribed, oval, smooth, firm, immobile, subcutaneous nodules ranging in size from 4 to 15 mm
Small, asymptomatic eyelid tumors can be followed conservatively, but for lesions that show significant growth, are painful, or cause ptosis or visual symptoms, surgical resection is indicated
The prognosis for eyelid lesions is excellent following adequate surgical resection
Benign peripheral nerve sheath tumors are divided into three broad categories: neuroma, neurofibroma, and schwannoma.1,2 Neurofibromas are tumors that arise from nonmyelinated axons, Schwann cells, fibroblasts, and perineural cells. Most neurofibromas are sporadic lesions, but multiple neurofibromas, plexiform neurofibromas, and large neurofibromas are almost always associated with neurofibromatosis type 1 (NF-1).3
Three distinct forms of neurofibroma are described: plexiform, diffuse, and solitary subtypes. Plexiform neurofibroma is mostly associated with NF-1 and is the most common benign peripheral nerve tumor occurring in the eyelid, where it typically tracks along peripheral branches of the trigeminal nerve. It can attain massive sizes and cause significant functional and cosmetic compromise (Chapter 93). Diffuse neurofibromas are uncommon, poorly defined, infiltrative cutaneous, subcutaneous, or soft-tissue tumors, seen most often in the head and neck of children and young adults. They extend between tissue planes, along connective tissue septa, and surround adjacent normal structures, encasing vascular and neural structures.4,5 Unlike the plexiform subtype, only about 10% of diffuse lesions are associated with neurofibromatosis.
Isolated neurofibromas are benign, slowly growing, unencapsulated neoplasms that usually arise from cutaneous nerves, with the occasional involvement of deep organs, bones, or nerves. They can be seen in patients with NF-1 where they tend to be multiple and are seen more commonly in deep locations. However, in most cases, isolated neurofibromas occur in patients who do not have NF-1, and in such cases, they are termed solitary neurofibroma.
The solitary neurofibroma is usually a well-circumscribed tumor that forms an ovoid or fusiform cutaneous or subcutaneous mass.6,7 As many as 90% of solitary lesions occur sporadically, while 10% are associated with NF-1 or NF-2.3,6 In the head and neck region, solitary neurofibromas most often involve the trigeminal (fifth) and facial (seventh) cranial nerves. The most frequently affected sites include the tongue, buccal mucosa, and lips,8,9,10,11 and deep lesions typically present as a facial mass.
Solitary neurofibroma of the eyelid is rare. Woog et al12 mentioned 65 cases of orbital and periorbital neurofibroma but without specific details. Of these cases, 40% were associated with NF-1, and 55% involved the eyelid. It was not clear how many of the eyelid cases were nonsyndromic or how many were plexiform vs solitary lesions.
To date, only 15 cases of solitary neurofibromatosis involving the eyelids have been described with sufficient clinical detail.13,14,15,16,17,18,19,20,21,22 Of these cases, 79% were female. The ages ranged from 38 to 81 years with a mean of 63.3 years. Lesions presented on the upper eyelid in 57% of the cases and the lower eyelid in 43%.
Neurofibroma involving the conjunctiva has also been described, of which 75% are solitary and 25% are syndromic.23,24,25,26,27,28,29,30,31,32,33,34,35,36 Conjunctival tumors occur equally among males and females, and the age at presentation is somewhat younger than for eyelid lesions, ranging from 22 to 78 years with a mean of 51 years.
Malignant transformation of a neurofibroma to malignant peripheral nerve sheath tumor is seen occasionally with plexiform neurofibromas but is exceptionally rare in solitary neurofibroma not associated with neurofibromatosis, although it can be seen with recurrent lesions.37
Etiology and Pathogenesis
The pathophysiology of both sporadic and syndromic cases of neurofibroma is similar and results from a deletion in the NF1 gene. In syndromic cases, the neurofibroma results from a germline mutation in the NF1 gene
on chromosome 17q11.2, which encodes the tumor suppressor protein neurofibromin.38,39 This genetic defect results in overexpression of the p21 RAS proto-oncogene, a cellular protein that plays a role in mitogenic signaling pathways. Heterozygous loss results in Schwann cell and fibroblast proliferation that forms neurofibromas. In sporadic cases, only the lesional cells and their somatic progeny carry the mutation.
on chromosome 17q11.2, which encodes the tumor suppressor protein neurofibromin.38,39 This genetic defect results in overexpression of the p21 RAS proto-oncogene, a cellular protein that plays a role in mitogenic signaling pathways. Heterozygous loss results in Schwann cell and fibroblast proliferation that forms neurofibromas. In sporadic cases, only the lesional cells and their somatic progeny carry the mutation.
 FIGURE 92.1 A and B, Solitary neurofibroma of the eyelids. |
Several studies have shown a loss of heterozygosity at the NF1 locus in dermal and plexiform neurofibromas,40,41,42,43 or inactivation of both copies of the NF1 gene in the NF1 gene in some isolated neurofibromas.43,44,45,46 Although some authors have suggested that sporadic neurofibromas may arise through a different genetic mechanism,47,48 Storlazzi et al49 showed that biallelic somatic inactivation of the NF1 gene through chromosomal translocation can lead to the cellular proliferation of Schwann cells associated with neurofibroma. Other chromosome studies of neurofibromas have reported clonally abnormal karyotypes, such as monosomy 22, hyperdiploid tumors, and complex translocations that may play a role in tumor growth.50,51,52,53,54,55 Marocchio et al56 considered that solitary neurofibroma may be a hyperplastic hamartomata rather than a neoplastic tumor.
Clinical Characteristics
Most neurofibromas involving the eyelid are solitary lesions and present as a circumscribed, oval, smooth, firm, immobile, subcutaneous nodule. Lesions are usually small, ranging in size from 4 to 15 mm in diameter with normal overlying skin (Figure 92.1). While generally painless, they may sometimes be tender or even painful. Lesions are slow growing over months to as long as 5 years.21 In patients with NF-1, cutaneous neurofibromas tend to be multiple58,59,60,61,62 and appear as discrete, subcutaneous nodules that can involve the eyelids and adjacent periorbital skin (Figure 92.2).
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