Neurothekeoma of the Cornea

The term neurothekeoma (NTK), first introduced by Gallager and Helwig [1 ]in 1980, has traditionally referred to a benign superficial cutaneous neoplasm of peripheral nerve sheath origin subclassified into histologic variants (cellular, myxoid, or mixed) depending on the degree of myxoid differentiation [2]. Nerve sheath myxoma (NSM), first described by Harkin and Reed [3] earlier in 1969, was classified as a subtype of NTK accounting for most of the neoplasms labeled as myxoid. This classification was later challenged due to inconsistent immunohistochemical similarities between NTK and NSM, and subsequently several retrospective case series demonstrated that the two entities were in fact separate based on consistent differences in their clinical, histologic, and immunohistochemical features [2,4,5]. In particular, lack of consistent S100 positivity among tumors labeled as cellular or myxoid NTK casts doubt upon whether the entity is of neural differentiation at all, with further staining indicating a possible ‘fibrohistiocytic' origin [5]. NTKs commonly present in patients as solitary nodular growths usually occurring in the head, neck, and upper extremities. In general, the occurrence of ocular tumors of nerve sheath origin is very rare, with neurofibroma being most commonly reported. Ocular NTKs are even more rare, being described only 11 times with the present case included, which reports the first case of cellular NTK involving the cornea. Despite the rarity, NTKs are benign and have a low rate of recurrence with complete excision regardless of location [5].

A 39-year-old Caucasian female presented to her optometrist with a white lesion on her left cornea. At that time, she was diagnosed with an infection and treated with Tobradex and Lotemax. On follow-up, the patient was found to have increased intraocular pressure secondary to the steroids and was treated with a course of Alphagan. Three months later, the patient presented to a corneal specialist with persistence of the lesion. She denied any pain, irritation, photosensitivity, or acute changes in vision. She previously wore contact lenses more than 10 years ago, otherwise her past ocular history was negative. The patient's past medical history was only significant for hypothyroidism treated with levothyroxine. She had no family history of ocular lesions, glaucoma, or macular degeneration and did not smoke cigarettes or drink alcohol. On exam, vision in the right eye was 20/20, and in the left eye, it was 20/50. Slit-lamp examination was within normal limits with the exception of a lesion on the left cornea. The lesion consisted of a white opaque and elevated pannus-like mass extending across the mid-periphery of the superior cornea from 10 to 2 o'clock. The superior margin was linear and fairly well defined, and the lesion did not extend to the limbus superiorly. The inferior margin was less opaque and scalloped, possibly encroaching on the visual axis. The lesion did not appear to cross the limbus temporally but seemed to extend to the nasal conjunctiva. The surrounding sclera and conjunctiva were clear, quiet, and noninjected.

Etiologies of corneal dystrophies and degenerations of the cornea were considered which included scaring from previous infection, limbal stem cell deficiency, band keratopathy, and stromal dystrophy. Given the quiet appearance of the eye, infectious and inflammatory etiologies of the lesion were lower on the differential diagnosis. Due to the clinical appearance, a preoperative diagnosis of Salzmann's nodular degeneration was made. Treatment options were discussed, and the patient elected surgical excision and underwent lamellar keratectomy for excision of the lesion.

The specimen was sent for pathologic examination. It consisted of a cellular proliferation (fig. 1a) composed of lobules and nests of epithelioid cells arranged in sheets (fig. 1b). These cells contained round to oval vesiculated nuclei, prominent nucleoli, and a moderate amount of eosinophilic cytoplasm (fig. 1c). Immunohistochemical stains were positive for microphthalmia transcription factor (MITF) (fig. 1d), CD68 (fig. 1e), CD10, NSE, SMA, and HAM56, and negative for S100 (fig. 1f), Melan A, HMB45, desmin, CK7, CK20, EMA, CD34, and CD1a. All above-mentioned pathologic features were diagnostic for cellular NTK.

The patient underwent the procedure without complications and was postoperatively treated with Vigamox q.i.d., prednisolone q.i.d., and oxycodone as needed. At the 1-week follow-up, vision in her left eye had improved to 20/25. After 3 months of follow-up, the lesion has not recurred, and the patient continues to maintain the improvement in visual acuity achieved postoperatively.

Despite an original classification as subtypes of a single entity, large series separately analyzing NTK and NSM have found clear differences in epidemiological, histological, immunohistochemical, and clinical features of the lesions [4,5,6] summarized in table 1. NTKs present as solitary, slow-growing dome-shaped papules involving the skin and superficial adipose layer [5]. These lesions show a 2:1 female-to-male predominance, occur in individuals with a mean age of 21-25 years, are found in the upper limb or head/neck in 68% of cases and in the distal extremities only in 17% of cases. Immunohistochemistry shows that NTKs tend to have positivity for NKI-C3, MITF, vimentin, and CD10 and are essentially universally negative for S100, GFAP, and desmin. Histologically, NTKs show myxoid features in 10% of cases, and the lobules of NTKs are typically poorly marginated and tend to infiltrate the surrounding dermal collagen or subcutaneous adipose tissue. Of clinical importance, the local recurrence rate for NTK is quite low (<8%) and was associated with incomplete excision in all cases. The cellular derivation of NTK is not clear, since histologic and immunohistochemical findings are neither specific nor conclusive. Fetsch et al. [5] have suggested a derivation from fibroblastic cells which can produce myxoid matrix and differentiate into myofibroblasts. Additionally, these authors indicate that NTK may have phagocytic properties that enable cells to recruit inflammatory or ‘histiocytic' cell types. This may explain the positivity for the histiocytic markers CD68 and HAM56 as demonstrated in the present case. Therefore, Fetsch et al. [5] concluded that the term ‘neurothekeoma' meaning ‘nerve sheath tumor' would be inappropriate and suggest the more descriptively accurate term ‘superficial micronodular (myxo/myo) fibroblastoma'.

Despite differences in epidemiological and diagnostic features, NSM should be included in the differential diagnosis of NTK, as the two lesions present with a similar clinical appearance. NSMs occur equally in males and females with a mean age of 36 years, are found in the upper limb or head/neck in only 12% of cases, and in the distal extremities in 86% of cases [4,5,6]. All these epidemiological parameters differ from NTK. On immunohistochemistry, NSMs show positivity for peripheral nerve sheath markers such as S100 and GFAP. Histologically, NSMs have a predominantly myxoid architecture in mostly 100% of cases and lobules that are usually sharply demarcated. Clinically, nearly 50% of NSM cases locally recur, with several cases recurring multiple times, which stands in contrast to the relatively low recurrence rate of NTK. The cellular derivation of NSM is established as peripheral nerve sheath based on consistent positivity with neural specific antigens such as S100 and GFAP.

Other lesions on the differential diagnosis of NTK include cutaneous myxoma/angiomyxoma, melanocytic lesions (melanoma and benign nevus), dermatofibroma, reticulohistiocytoma, and plexiform fibrohistiocytic tumor (PFT). The histological and immunohistochemical findings [5] of these lesions are summarized in table 2.

Cutaneous angiomyxoma can be differentiated from NTK by CD34 positivity and a much higher reported recurrence rate (30-40 vs. <8%) [5]. Melanocytic lesions, most commonly Spitz nevus but also malignant melanoma, carry similar histological and epidemiological features as NTK. Additionally, there is overlap in immunohistochemical features, with both lesions demonstrating positivity for MITF and NKI-C3. MITF and NKI-C3 (also known as CD63) show reactivity in cells undergoing melanogenesis. Unexpected MITF and NKI-C3 positivity in NTK has been postulated by Fetsch et al. [5] as being a ‘false positive' result due to unexplained cross-reactivity. Despite this immunohistochemical overlap, melanocytic tumors can be differentiated from NTK mainly by consistent S100 positivity. Furthermore, NTK are consistently negative for other ‘melanocytic' markers such as HMB45, Melan A, and tyrosinase.

Dermatofibromas differ from NTK mainly in morphology, as these lesions demonstrate elongated nuclei and scant cytoplasm [7]. Reticulohystiocytomas (solitary epithelioid histiocytomas) differ from NTK in that they rarely show whorled growth and cytoplasmic retractions with filopod extensions, and rarely demonstrate nuclear atypia. Additionally, they show strong positivity for CD163 and CD68 and, in some cases, focal positivity for S100 [8].

PFT may be difficult to differentiate from NTK based on epidemiological features and immunohistochemistry [9]. Distinction relies on morphology, as PFTs will often spare the upper dermis and have more subcutaneous invasion than NTK. Tumor cells in PFT will be better defined and demarcated and lack the nuclear variability often seen in NTK. This distinction is important, as PFTs have been reported to rarely metastasize.

Ocular NTK are extremely rare neoplasms (table 3) having only been reported 11 times and usually occurring in the eyelid, with the exception of 1 case which occurred within the orbit and the present case with a corneal NTK [6,10,11,12,13,14,15,16,17,18]. The mean age among the 11 cases is 33.5 years, which is higher than in nonocular NTK (21-24 years). Preoperative diagnoses were chalazion, fibroma, or epidermal inclusion cyst for the eyelid lesions and Salzmann's nodular dystrophy for the present corneal case. Complete excision of these lesions is needed as recurrence and re-excision was reported in 2 of the cases [7,12]. Despite their rarity, NTK should remain on the differential diagnosis of any solitary, nodular mass of the eyelid or orbit. Additionally, with appropriate history and presentation (noninfectious/inflammatory), these lesions can be included in the differential of a corneal lesion or neoplasm.

Supported in part by NIH NEI P30EY06360 grant and a Departmental grant from Research to Prevent Blindness, Inc.

This is a single case report and our university's IRB does not require approval for single case reports (i.e. it has IRB exempt status). No animals were used in our study.

The authors declare that there are no conflicts of interest.