Neurothekeoma

Etiology

There has been considerable confusion in characterizing and defining the origin of neurothekeomas. In 1980, Gallager and Helwig first classified neurothekeomas as dermal tumors of neural origin with characteristic clinical features and distinctive histology. Clinical features included a flesh-colored or slightly erythematous nodule of soft consistency located on the head, upper extremities, or trunk and arising more commonly in young females. Histologic features included spindled cells arranged in nests and cords with a mucinous, myxoid background containing dermal collagen bundles. Because the tumor cells appear similar to Schwann cells on electron microscopy (spindle-shaped and surrounded by a basement membrane without myofilament or melanosomes), the authors proposed "neurothekeoma" from the Greek word for sheath.[7] In 1986, Rosati et al reported cases of cellular neurothekeoma, believing them to be a cellular variant of the previously reported myxoid neurothekeoma.[8] In 1990, Barnhill and Mihm reported on several cases of cellular neurothekeoma, remarking on their histologic similarity to melanocytic tumors as well as commenting on their failure to react with S100 protein immunostain, unlike the original reported myxoid variant of neurothekeoma. Barnhill and Mihm suggested that cellular neurothekeoma represented a distinct subcategory of neurothekeoma and then, in 1991, suggested that cellular neurothekeoma might present an entirely separate entity.[1][9] It is recognized now that at least some of the cases reported by Gallager and Helwig in 1980, as well as some subsequent reports of neurothekeoma, represented dermal nerve sheath myxoma, an entity of peripheral nerve sheath derivation that shares overlapping clinical and histologic features with neurothekeoma.[3][4][7][4][10] In 2005, Fetsch et al reported on a series of nerve sheath myxomas, the corresponding characteristic immunoprofile, and the tendency of nerve sheath myxoma to arise in different locations and exhibit a higher recurrence rate than neurothekeoma.[11] In 2007, 2 large case studies of neurothekeomas were published separately by Fetsch et al and Hornick and Fletcher, detailing the immunoprofile of neurothekeoma, further defining the entity as distinctive and separate from nerve sheath myxoma.[3][4] Rather than displaying nerve sheath differentiation, it has been postulated that neurothekeoma is fibrohistiocytic.[3][4][5][6]

Epidemiology

Epidemiologically, females outnumber males almost 2 to 1, and although a wide age range has been reported, the tumor displays a strong predilection for the second and third decades of life.[3][4][10][12][13]

Histopathology

Neurothekeomas are classified histologically as myxoid, cellular, or mixed, depending on the amount of myxoid matrix.[3][4][5][6][13][6] The classical cellular neurothekeoma is a relatively circumscribed and lobular lesion in the dermis, although the lesion's periphery may have an infiltrative border. It typically comprises nests of epithelioid to slightly spindled tumor cells with a subtle whorling pattern. The tumor cells have relatively abundant eosinophilic cytoplasm and round to oval nuclei with small pinpoint nucleoli.[2][4][5][7][14] By immunohistochemistry, cellular neurothekeomas are typically positive for vimentin, NKI-C3 (CD63), CD10, and Mit-F, and focal reactivity is noted for smooth muscle actin and CD68. They are negative for S100, glial fibrillary acidic protein, and Melan A.[3][14][15]

History and Physical

Lesions are often a singular subcutaneous dome-shaped papule or nodule measuring less than 2 cm and may be skin-colored, pink to tan, or red to brown. Most lesions are asymptomatic, although some may present with pain upon pressure. The lesions grow slowly and are usually superficially located, with rare, deeper subcutaneous fat or skeletal muscle involvement. The head and neck are the most common locations, but neurothekeomas may also be seen on the shoulder or upper extremities.[3][4][8][13][14] Mucosal involvement is rare.[16]

Evaluation

Clinicopathologic correlation is required for the correct diagnosis of a neurothekeoma. If the lesion appears very superficial, a shave biopsy may be appropriate; however, since these are usually dermal nodules with the possibility of deeper involvement, a deep punch, incisional, or excisional biopsy may be a better option. The chosen skin biopsy technique varies depending on the size and location of the lesion. When the lesion is small, easily palpable, and not located in a cosmetically or functionally sensitive area, imaging is not generally necessary. There are no known pathognomic radiologic findings; computed tomography (CT), magnetic resonance (MR), and fluorodeoxyglucose positron emission tomography (FDG PET) imaging may be helpful adjuncts for surgical planning and clinical correlation. However, histology remains the gold standard for diagnosis.[17]

Treatment / Management

Surgical excision is the primary method of treatment.[18] There is no consensus on excision margin, but clear microscopic margins and a few millimeters of grossly negative margins are sufficient.[18] If the neurothekeoma is located in a cosmetically sensitive area, Mohs micrographic surgery may be used to achieve margin control while sparing the normal surrounding tissue.[13] While the majority of these tumors are small (less than 1 cm) and have relatively bland histology with scant to no cytologic atypia and minimal extension into surrounding fat or skeletal muscle, there have been reports of neurothekeomas displaying atypical features, increasing concern for aggressive potential.[15][19] Reported atypical features include clinical size greater than 1 cm, cytologic atypia in the form of pleomorphism and increased mitotic activity, infiltration into skeletal muscle or subcutaneous fat, and vascular invasion. Regardless of atypical features, reported recurrence rates remain low following complete surgical excision.[3][4][13][15][19](B3)

Differential Diagnosis

The differential diagnosis for an epithelioid mass in the head and neck region includes granular cell tumor, cellular neurothekeoma, nerve sheath myxoma, neurofibroma, schwannoma, benign fibrous histiocytoma, melanocytic lesions, for example, Spitz nevus or melanoma, and infection.[2][3][4] The absence of bacterial or fungal elements on routine and special stains can rule out infectious etiologies. Granular cell tumors typically are positive for S100 protein immunostain; therefore, this entity can be ruled out with a negative S100 stain. The remaining entities on the list are neural (neurofibroma, schwannoma, nerve sheath myxoma), fibrohistiocytic (neurothekeoma, fibrous histiocytoma), or melanocytic and can all present similarly as solitary masses. Furthermore, these entities may mimic each other histologically.

Distinguishing neural and fibrohistiocytic lesions from malignancies like melanoma can be difficult given the variable presence of epithelioid cells arranged in a cheque-like architecture and given the potential presence of unusual features such as nuclear atypia, mitoses, and extension into fat or skeletal muscle.[2][3][4] Careful inspection of morphology can help distinguish fibrohistiocytic lesions from each other. For instance, recognizing at least focal areas of a nested growth pattern characteristic of conventional cellular neurothekeoma helps distinguish it from superficial angiomyxomas or benign fibrous histiocytomas, which lacks nests of tumor cells.[14] However, because of this nested growth pattern, a melanocytic tumor or Spitz nevus could still be considered in the differential. The immunoprofile is telling in these cases because cellular neurothekeomas are negative for S100 and melanocyte-specific markers such as Melan-A and HMB-45, unlike true melanocytic tumors.[14]

The most problematic delineation is between cellular neurothekeoma and nerve sheath myxoma because of overlapping clinical presentation and histology. In the past, nerve sheath myxoma has been inadvertently included within the myxoid variant of neurothekeoma.[2]  Immunohistochemistry helps distinguish true nerve sheath myxoma from neurothekeoma. Nerve sheath myxomas are consistently positive for S100 and negative for NKI-C3, whereas cellular neurothekeomas show the opposite immunostaining pattern of S100 negativity and NKI-C3 positivity.[2][3] The other neural lesions on the differential (schwannoma and neurofibroma) can be differentiated via morphology and immunostaining. Schwannomas have a biphasic growth pattern and are positive for S100, GFAP, and EMA. Neurofibromas are positive for S100.

Prognosis

As neurothekeoma is considered a benign entity, the prognosis is excellent, with very low recurrence rates following complete surgical excision.[3][4][13][15][19]

Complications

As most neurothekeomas are confined within the dermis, complications are generally minor and cosmetic related to the surgical scar. For lesions with subcutaneous extension beyond the fat and into the skeletal muscle, there may be a risk of localized weakness related to the extent of musculature removed with excision.