Neurofibroma is the second most common peripheral nerve sheath tumor and closely related to the schwannoma. The main distinguishing factors, however, are more intimate involvement of the parent nerve and a greater relationship to neurofibromatosis-1. Neurofibromas may occur at any age but are most predominant in patients 20–40 years of age. Presenting symptoms are similar to other nerve tumors with early painless growth followed by neuropathic symptoms from nerve compression. Tinel’s sign is frequently positive with reports of 100% presence in neurofibroma. Up to 33% may also present with motor deficits [13]. The majority of neurofibromas are sporadic lesions, but approximately 10% present in patients with neurofibromatosis-1 [13].

Neurofibromatosis-1 (NF-1) is an autosomal dominant inherited neurocutaneous disease with a large spectrum of clinical manifestations. The NF-1 gene on chromosome 17 has been found to be the genetic basis of NF-1 with mutations leading to decreased function of the neurofibromin protein. While the exact genetic pathogenesis remains elusive, the protein is known to be part of the Ras signaling pathway with decreased levels leading to clinical NF-1 [14]. The diagnosis is confirmed when patients have two of the following: six or more cafe-au-lait spots, a plexiform neurofibroma or two neurofibromas, axillary or inguinal freckling, Lisch nodules, optic gliomas, or orthopedic manifestations. The bony lesions seen in neurofibromatosis-1 include sphenoid wing dysplasia, congenital tibial pseudarthrosis, and scoliosis. Patients with neurofibromatosis-1 carry about a 10% risk of malignant transformation of their neurofibromas [15, 16].

Both solitary and NF-1-associated neurofibromas can be classified into four major categories: localized intraneural, localized cutaneous, diffuse neurofibroma, and plexiform. Localized intraneural neurofibroma is the most common entity and presents as a nodular expansion in the peripheral nerve. Diffuse neurofibroma typically involves subcutaneous tissues rather than major peripheral nerves. The plexiform subtype is pathognomonic for NF-1 and accordingly carries a higher risk for malignant transformation. This subtype involves multiple nerve branches and is classically described as a “bag of worms” [1, 15].

In the upper extremity, neurofibromas appear to have a predilection for small nerve branches. In Gosk’s review of 72 upper extremity nerve tumors, only 12 of the 51 major nerve tumors were neurofibromas, while 39 of the 50 small nerve tumors were neurofibromas [3].

The work-up for neurofibroma is similar to all suspected nerve tumors with MRI as the gold standard for imaging. Similar to the schwannoma, neurofibromas appear as growths from the parent nerve with low or medium intensity on T1 and high intensity on T2. The target sign, an axial image of central low intensity with surrounding high intensity, has been shown to be nonspecific but still classically associated with neurofibroma [13].

On gross pathology, neurofibromas tend to be unencapsulated and are intimately involved with the nerve fascicles. Unlike the eccentric growth of schwannomas, neurofibromas are more likely to have fusiform growth with entanglement of the nerve fascicles. Biopsy provides definitive diagnosis of the neurofibroma with several distinguishing factors. Unlike the schwannoma, neurofibromas have a more heterogeneous cell population with fibroblasts and Schwann cells contributing to the tumor (Fig. 29.4). Thus, the histology appears more myxoid and has more variable staining with S100 unlike the homogenous S100 staining of schwannoma [14, 15].

Due to the greater involvement of nerve fascicles, enucleation of the neurofibroma is technically more challenging and sacrifice of functional nerve is considered likely. As a result, more conservative measures are indicated, and surgery is delayed unless pain is intolerable. In one series of 37 neurofibromas, only 8% could be resected without any nerve damage. Sixteen percent sustained significant damage involving more than two fascicles; 33% of the total cases required nerve grafting or direct repair due to excision of functional fascicles. Motor function is commonly lost with reports describing 15–50% of patients having loss of at least one motor strength [3, 17]. Nerve repairs and grafts have not been shown to definitively improve or sustain function but do serve to reduce painful neuroma formation and are therefore recommended. Several reports advocate the use of intraoperative neural monitoring for neurofibroma excision as an effort to minimize trauma to the functional nerve. However, when performed for pain relief, neurofibroma excision appears to have varied efficacy with reports of 50–100% pain relief [3, 17].

The lipofibromatous hamartoma (LFH ) is a tumor of unknown origin that preferentially affects the median nerve, typically in the palm or forearm. Most cases present before age 30, with an equal incidence in both genders. The most common presenting symptom is a soft, mobile, nontender, nonfluctuant mass in the volar forearm, wrist, or hand. Symptoms from nerve compression may also occur with tumor growth but paresthesia has been reported to present in only 39% of patients [18].

Up to two-thirds of patients also have macrodactyly in the involved region, although researchers have advocated classifying the presence of macrodactyly as a separate variant of lipofibromatous hamartoma [18, 19]. The hypertrophy of all tissues such as adipose, muscle, and skeletal in a particular neural distribution has led to a classification as “macrodystrophia lipomatosa .” While definitive basic science research is lacking, researchers have hypothesized “sclerotomes” in addition to dermatomes and myotomes that may respond to pathology in a particular nerve branch with hyperplasia in the given innervated area. A case of “dual pathology” to the median nerve in which the patient had a distal LFH in addition to compression on the median nerve from coronoid osteochondroma has been debated as an example of this nerve-distributed macrodactyly [20, 21].

Ultrasound may be used in the diagnosis of this tumor, especially since the major differential diagnosis includes hemangiomas and ganglion cysts which may be readily diagnosed with ultrasound. LFH on ultrasound is described as a fusiform mass with longitudinal nerve bundles and alternating hypoechoic and hyperechoic bands. However, as with all nerve tumors, MRI remains the imaging gold standard. LFH is commonly seen as a fusiform or hourglass enlargement of the nerve on coronal sections with serpentine nerve bundles surrounded by fat, leading to a “spaghetti-like” appearance. On axial views, the tumor is described as a “coaxial cable” with nerve bundles separated by fat [18, 19]. These findings are pathognomonic for LFH, and given the possibility of nerve compromise with biopsy, invasive diagnostics is typically not necessary or recommended.

While not routinely performed for diagnostic purpose, histology will also confirm LFH as a tumor characterized by mature adipose and fibrous tissue infiltrating the potential space between the epineurium and perineurium of nerve fascicles.

As described by Tahiri, the treatment of LFH follows four major treatment goals: symptom prevention, symptom relief, aesthetic concerns, and avoidance of functional impairment [18]. Currently, treatment paradigms appear to be more conservative in nature with expectant management until symptom presentation as the prevailing treatment. Once indicated, the most common treatment modalities are carpal tunnel release for decompression to alleviate neuropathy. Resection of the tumor may not represent a cure in comparison to other nerve neoplasms. Mahan and colleagues reported a case wherein LFH recurred at the nerve graft with fibrofatty proliferation throughout the graft and its distal branches. The authors speculate that microscopic residual tumor is present despite a macroscopic total resection, allowing for progression and recurrence of tumor [22]. In the presence of macrodactyly, epiphysiodesis may be attempted in skeletally immature patients. In adults with severely limiting macrodactyly, surgeons may perform arthroplasty or may even consider ray amputations [18].