Continuing Education Activity

Neurothekeomas are rare, benign, superficial cutaneous tumors with variable histologic patterns, including myxoid, cellular, or mixed-type based primarily on the amount of myxoid matrix present. 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. This activity illustrates the evaluation, treatment, and complications of neurothekeomas and the importance of an interprofessional team approach to management.

Objectives:

• Review the definition of a neurothekeoma.
• Describe the typical presentation of a neurothekeoma.
• Explain how to manage neurothekeomas.
• Outline a well-coordinated interprofessional team approach to provide effective care to patients affected by neurothekeomas.

Introduction

Neurothekeomas are rare, benign, superficial soft tissue tumors that most commonly occur on the head and neck. They tend to affect females more often than males, usually in the second and early third decades of life.[1] Neurothekeoma clinically presents as a skin-colored, pink, red, or brown well-circumscribed papule or nodule. Usually, they are asymptomatic but may be accompanied by pain with pressure. Neurothekeomas have 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 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.[2] Rather than arising from peripheral nerve sheath, it has been postulated that neurothekeomas are of fibrohistiocytic derivation.[3][4][5][6] While nerve sheath myxoma demonstrates immunoreactivity for S100 protein, neurothekeoma fails to react with S100 regardless of the histologic pattern (myxoid, mixed, or cellular).

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 the name “neurothekeoma” from the Greek word for sheath.[7] 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.[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 sub-category 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][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 in nature.[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][13][6] 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.[2][7][4][5][14]  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.[15][3][14]

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 tend to grow slowly and are usually superficially located, with rare, deeper involvement of subcutaneous fat or skeletal muscle. The head and neck are the most common locations, but neurothekeomas may also be seen on the shoulder or upper extremities.[3][4][13][8][14] Mucosal involvement is rare.[16]

Evaluation

Clinicopathologic correlation is required for the correct diagnosis of a neurothekeoma. If the lesion appears to be 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 will vary 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 although histology will remain 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 thought to be sufficient.[18] If the neurothekeoma is located on 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 the presence of atypical features, reported recurrence rates remain low following complete surgical excision.[3][4][13][4][15][19]

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] 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 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 theque-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, recognition of 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 will lack 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. 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.[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][4][15][19]

Complications

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

Deterrence and Patient Education

As the pathogenesis of neurothekeoma remains unclear, there is currently no guidance that can be provided to patients regarding the prevention of such lesions.

Pearls and Other Issues

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 are generally immunoreactive with CD10, CD68, MITF-1, and NKI-C3 and negative for NSE, S100 protein, or GFAP. The recommended treatment for neurothekeoma is complete surgical excision; recurrence rates are low even for tumors demonstrating atypical features. Head and neck surgeons and pathologists need 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.

Enhancing Healthcare Team Outcomes

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.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Barnhill RL, Mihm MC. Cellular neurothekeoma. A distinctive variant of neurothekeoma mimicking nevomelanocytic tumors. Am J Surg Pathol. 1990 Feb;14(2):113-20. [PubMed: 2154139]

2.

Almeida TFA, Verli FD, Dos Santos CRR, Falci SGM, Almeida LY, Almeida LKY, Mesquita ATM, León JE. Multiple Desmoplastic Cellular Neurothekeomas in Child: Report of the First Oral Case and Review of the Literature. Head Neck Pathol. 2018 Mar;12(1):75-81. [PMC free article: PMC5873483] [PubMed: 28597210]

3.

Fetsch JF, Laskin WB, Hallman JR, Lupton GP, Miettinen M. Neurothekeoma: an analysis of 178 tumors with detailed immunohistochemical data and long-term patient follow-up information. Am J Surg Pathol. 2007 Jul;31(7):1103-14. [PubMed: 17592278]

4.

Hornick JL, Fletcher CD. Cellular neurothekeoma: detailed characterization in a series of 133 cases. Am J Surg Pathol. 2007 Mar;31(3):329-40. [PubMed: 17325474]

5.

Page RN, King R, Mihm MC, Googe PB. Microphthalmia transcription factor and NKI/C3 expression in cellular neurothekeoma. Mod Pathol. 2004 Feb;17(2):230-4. [PubMed: 14685254]

6.

Yun SJ, Park HS, Lee JB, Kim SJ, Lee SC, Won YH. Myxoid Cellular Neurothekeoma: A New Entity of S100-Negative, CD68-Positive Myxoid Neurothekeoma. Ann Dermatol. 2014 Aug;26(4):510-3. [PMC free article: PMC4135109] [PubMed: 25143683]

7.

Gallager RL, Helwig EB. Neurothekeoma--a benign cutaneous tumor of neural origin. Am J Clin Pathol. 1980 Dec;74(6):759-64. [PubMed: 7446487]

8.

Rosati LA, Fratamico FC, Eusebi V. Cellular neurothekeoma. Appl Pathol. 1986;4(3):186-91. [PubMed: 3297114]

9.

Barnhill RL, Dickersin GR, Nickeleit V, Bhan AK, Muhlbauer JE, Phillips ME, Mihm MC. Studies on the cellular origin of neurothekeoma: clinical, light microscopic, immunohistochemical, and ultrastructural observations. J Am Acad Dermatol. 1991 Jul;25(1 Pt 1):80-8. [PubMed: 1880258]

10.

Li J, Shi Z, Jing J. Neurothekeomas of the thoracic and lumbar area in an adult man: A case report. Mol Clin Oncol. 2014 Jan;2(1):156-158. [PMC free article: PMC3915694] [PubMed: 24649326]

11.

Fetsch JF, Laskin WB, Miettinen M. Nerve sheath myxoma: a clinicopathologic and immunohistochemical analysis of 57 morphologically distinctive, S-100 protein- and GFAP-positive, myxoid peripheral nerve sheath tumors with a predilection for the extremities and a high local recurrence rate. Am J Surg Pathol. 2005 Dec;29(12):1615-24. [PubMed: 16327434]

12.

Suarez A, High WA. Immunohistochemical analysis of KBA.62 in 18 neurothekeomas: a potential marker for differentiating neurothekeoma, but a marker that may lead to confusion with melanocytic tumors. J Cutan Pathol. 2014 Jan;41(1):36-41. [PubMed: 24151815]

13.

Ward JL, Prieto VG, Joseph A, Chevray P, Kronowitz S, Sturgis EM. Neurothekeoma. Otolaryngol Head Neck Surg. 2005 Jan;132(1):86-9. [PubMed: 15632914]

14.

Stratton J, Billings SD. Cellular neurothekeoma: analysis of 37 cases emphasizing atypical histologic features. Mod Pathol. 2014 May;27(5):701-10. [PubMed: 24186141]

15.

Busam KJ, Mentzel T, Colpaert C, Barnhill RL, Fletcher CD. Atypical or worrisome features in cellular neurothekeoma: a study of 10 cases. Am J Surg Pathol. 1998 Sep;22(9):1067-72. [PubMed: 9737238]

16.

Emami N, Zawawi F, Ywakim R, Nahal A, Daniel SJ. Oral cellular neurothekeoma. Case Rep Otolaryngol. 2013;2013:935435. [PMC free article: PMC3638503] [PubMed: 23691398]

17.

Kim HJ, Baek CH, Ko YH, Choi JY. Neurothekeoma of the tongue: CT, MR, and FDG PET imaging findings. AJNR Am J Neuroradiol. 2006 Oct;27(9):1823-5. [PMC free article: PMC7977873] [PubMed: 17032850]

18.

Boukovalas S, Rogers H, Boroumand N, Cole EL. Cellular Neurothekeoma: A Rare Tumor with a Common Clinical Presentation. Plast Reconstr Surg Glob Open. 2016 Aug;4(8):e1006. [PMC free article: PMC5010351] [PubMed: 27622087]

19.

Wilson AD, Rigby H, Orlando A. Atypical cellular neurothekeoma--a diagnosis to be aware of. J Plast Reconstr Aesthet Surg. 2008;61(2):186-8. [PubMed: 17709307]

Disclosure: Erica Kao declares no relevant financial relationships with ineligible companies.

Disclosure: Mikelle Kernig declares no relevant financial relationships with ineligible companies.