Neurothekeomas are rare, benign, superficial, soft tissue tumors of unknown histogenesis, although fibrohistiocytic derivation has been suggested. On histology, the cellular variant of neurothekeoma will appear as a bland, cellular, epithelioid proliferation that demonstrates strong immunoreactivity for vimentin, MITF-1, CD10, and NKI-C3. Neurothekeomas are classically described as benign, superficial cutaneous tumors with variable histologic patterns, including myxoid, cellular, or mixed-type based primarily on the amount of myxoid matrix present. Because of overlapping clinical presentation and histology, nerve sheath myxoma has, in a past case study series, been inadvertently included within the myxoid variant of neurothekeoma. However, neurothekeoma, as described by Barnhill and Mihm in 1990, appears to be a separate and distinct entity from true nerve sheath myxoma. While nerve sheath myxoma demonstrates immunoreactivity for S-100 protein, neurothekeoma fails to react with S-100 regardless of the histologic pattern (myxoid, mixed, or cellular). Rather than arising from peripheral nerve sheath, it has been postulated that neurothekeomas are of fibrohistiocytic derivation.,,, They frequently occur in the head and neck and tend to affect females more often than males, usually in the second and early-third decades of life .
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 the name “neurothekeoma” from the Greek word for sheath. In 1986, Rosati et al. reported cases of what they termed cellular neurothekeoma, believing them to be a cellular variant of the previously reported myxoid neurothekeoma. 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 S-100 protein immunostain, unlike the original reported myxoid variant of neurothekeoma. Barnhill and Mihm suggested that cellular neurothekeoma represented a distinct sub-category of neurothekeoma, and then in 1991, suggested that cellular neurothekeoma might present an entirely separate entity.,. 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.,,, 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.. In 2007, 2 large case studies of neurothekeoma 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., Rather than displaying nerve sheath differentiation, it has been postulated that neurothekeoma is fibrohistiocytic in nature.,,,
Neurothekeomas were initially classified histologically as myxoid, cellular, or mixed depending on the amount of myxoid matrix . The classical cellular neurothekeoma is a relatively circumscribed and lobular lesion in the dermis although the periphery of the lesion may have an infiltrative border. It is typically composed of 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 . By immunohistochemistry, cellular neurothekeomas are typically positive for vimentin, NKI-C3 (CD63), CD10, 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 . In almost all cases, cellular neurothekeoma is positive for the combination of NKI-C3 and CD10 .
Clinically, neurothekeomas are usually asymptomatic and found in the skin and the superficial dermis. Mucosal involvement is rare. Patients typically present with a solitary mass measuring less than 2.0 cm, appearing dome-shaped, popular, or nodular with a pink-tan to reddish-brown. The lesions tend to grow slowly and are usually superficially located, with rare, deeper involvement of skeletal muscle or subcutaneous fat. Patients tend to be young females and typically present with an asymptomatic, slow-growing solitary dermal nodule of the head and neck, shoulder, or upper extremities measuring less than 2 cm.,,,,
Treatment consists of surgical excision. There is no consensus on excision margin, but clear microscopic margins and a few millimeters of grossly negative margins are thought to be sufficient. 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., 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 the presence of atypical features, reported recurrence rates remain low following complete surgical excision.,,,,
The differential diagnosis for an epithelioid mass in the head and neck region include granular cell tumor, cellular neurothekeoma, nerve sheath myxoma, neurofibroma, schwannoma, benign fibrous histiocytoma, melanocytic lesions, for example, Spitz or melanoma, and infection.,,. Infectious etiologies can be ruled out by the absence of bacterial or fungal elements on routine and special stains. Granular cell tumors typically are positive for S-100 protein immunostain; therefore, this entity can be ruled out with a negative S-100 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 theque-like architecture and given the potential presence of unusual features such as nuclear atypia, mitoses, and extension into fat or skeletal muscle.,, Careful inspection of morphology can help distinguish fibrohistiocytic lesions from each other. For instance, recognition of at least focal areas of a nested growth pattern characteristic of conventional cellular neurothekeoma helps distinguish this entity from superficial angiomyxomas or benign fibrous histiocytomas, which will lack nests of tumor cells.. However, because of this nested growth pattern, melanocytic tumors or Spitz nevus could still be considered in the differential. In these cases, the immunoprofile is telling because unlike true melanocytic tumors, cellular neurothekeomas are negative for S100 and melanocyte-specific markers such as Melan-A and HMB-45.
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. 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.,, 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.
In conclusion, neurothekeomas are rare, superficial tumors most often arising in the head and neck, shoulder, or upper extremities of younger females. The tumors tend to be small, less than 2 cm, and histologically are composed of a mix of spindled and epithelioid cells set against a variably myxoid background stroma. The neoplastic cells have been shown to be generally immunoreactive with CD10, CD68, MITF-1, and NKI-C3 and negative for NSE, S-100 protein, or GFAP. The recommended treatment for neurothekeoma is complete surgical excision; recurrence rates are low even for tumors demonstrating atypical features. It is important for head and neck surgeons and pathologists to be aware of the presentation and clinical course of this uncommon lesion, as well as its similarity to other benign and malignant tumors clinically and histologically, to adequately manage patients and provide appropriate treatment options and follow-up care.
Because neurothekeomas are benign entities that are curative with surgical excision, the best patient outcomes can be achieved with an interprofessional care team of radiologists, surgeons, pathologists, primary care providers, and nurses who are cognizant of the specific clinical presentation and characteristic patient demographics. This will aid in early recognition and proper management of this lesion. Furthermore, neurothekeomas can masquerade as other more aggressive malignancies. Thus, recognizing the morphologic and biologic spectrum of neurothekeoma and its variants helps the health care professional team render the most accurate diagnosis ultimately, and most importantly, for the patient's peace of mind.
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