Epithelial Sheath Neuroma of the Back: A Rare Mimicker of Perineural Invasion in Cutaneous Malignancy

Background: Perineural invasion (PNI) is typically considered a hallmark of malignancy in epithelial neoplasms. However, benign conditions can also demonstrate perineural epithelial involvement, which may lead to diagnostic confusion. Epithelial sheath neuroma (ESN) is an exceedingly rare benign cutaneous lesion characterized by enlarged nerve bundles ensheathed by squamous epithelium.

Case Presentation: We describe a 43-year-old male presenting with a 2 cm, asymptomatic, erythematous nodule on the back of three years’ duration. Histopathological examination of the excised lesion revealed multiple thickened nerve bundles ensheathed by bland squamous epithelium within the superficial dermis, in the absence of connection to the epidermis or adnexal structures. No cytologic atypia or evidence of malignancy was present.

Discussion: The morphological features were consistent with ESN. Key differential diagnoses include perineural invasion by squamous cell carcinoma, re-excision perineural involvement (RPI), and reactive neuroepithelial aggregates (RNEAs). The distinction from these entities is critical to avoid overdiagnosis and overtreatment. The pathogenesis of ESN remains speculative, with proposed theories including metaplastic transformation, neural crest origin, and reactive hyperplasia secondary to local inflammation.

Conclusion: ESN, though rare, should be recognized as a benign mimic of malignant PNI. Awareness among dermatologists and pathologists is essential to prevent misinterpretation and unnecessary aggressive management. This case contributes to the growing body of literature on ESN and underscores the need for further investigation into its histogenesis.

Perineural involvement by epithelial cells is usually considered as a sign of malignancy. In the skin, the highest incidence of perineural invasion (PNI) by epithelial malignancy is seen in primary cutaneous adenoid cystic carcinoma (50%), squamous cell carcinoma (2.5-14%), keratoacanthoma (14%) and basal cell carcinoma (3-10%) [1]. In most of these tumours PNI is usually considered an indicator of aggressive behaviour and poor prognosis [2,3] with the presence of some exceptions [4]. On the other hand, perineural involvement is not entirely exclusive to malignant conditions. It can be seen in association with benign neoplasms and non-neoplastic conditions in the skin [5,6] and in other tissues as well [7-9]. Requena and colleagues described what they believed to be a benign cutaneous neoplasm characterised by the presence of enlarged nerve bundles ensheathed by squamous epithelium and located in the superficial dermis. They called this lesion epithelial sheath neuroma ESN [10].

We describe a case of ESN accompanied by the differential diagnoses and discussion of its possible pathogenesis.

A 43-year-old male presented with a 3-year history of 2cm solitary, erythematous nodule on his back. It was neither itchy nor painful and the surface was not ulcerated. Initially, topical steroid cream for 6 months was given, with no response. According to the patient, the size of the lesion did not increase significantly since the initial presentation. There was no previous history of local trauma or surgical procedures. The patient had no past medical history of malignancy or any skin condition. The lesion was excised with a 2mm margin, fixed in 10% formalin and embedded in paraffin. Histological sections were stained with H&E.

Table 1: Characteristics of ESN cases reported to date.

Microscopic picture

The superficial dermis contained multiple thickened nerve bundles, majority of which are ensheathed by a circumferential or sometimes incomplete mantle of bland squamous epithelial cells focally exhibiting orthokeratosis hyperkeratosis. The enlarged nerve bundles were arranged in random directions but predominantly parallel to the epidermis. The stroma around these neuroepithelial structures was slightly myxoid and contained a mild to moderate lymphocytic infiltrate.  Several serial sections failed to reveal any communication between these neuroepithelial structures and the overlying epidermis, which was normal, or adjacent hair follicles.

Figure 1: (A) Low magnification showing multiple thickened nerves ensheathed by stratified squamous epithelium in the superficial dermis. Note the normal epidermis and the absence of scarring. (B) Higher magnification showing the neuroepithelial structures surrounded by a lymphocytic infiltrate.

Follow Up: No evidence of recurrence or new lesions during a (12 months) follow up period.

The presence of neuroepithelial structures in histological specimens does not always mean perineural invasion. Epithelial sheath neuroma is a recently described benign entity with a characteristic clinicopathological attributes.

The most important differential diagnosis of ESN is perineural invasion (PNI) by squamous cell carcinoma or keratoacanthoma. The involved nerves in these conditions are not usually enlarged. Moreover, SCCs demonstrating PNI are usually poorly differentiated with rare keratinisation [1]. On the other hand, ESN develops with no prior history of tumours or evidence of scarring which may suggest a regressed tumour. The second differential diagnosis is reexcision perineural invasion (RPI) described by Stern and Haupt [11]. It is the perineural involvement by non-neoplastic squamous epithelium in the skin reexcision specimens. Their report included 2 patients with previously excised melanocytic lesions. For the diagnosis of RPI, they recommended specific criteria: perineural involvement should be limited to the immediate previous biopsy site, perineural epithelial cells should have a benign appearance different from the appearance of the original tumour and no residual epithelial tumour should be present adjacent to the neuroepithelial lesion [11]. According to these criteria Stern and Haupt [12] rejected the suggestion of Wu et al. that cytological atypia may be seen in RPI [13]. Epithelial sheath neuroma can be differentiated from RPI by the absence of history of previous local excision and the lack of any evidence of scarring in histological sections.

Reactive neuroepithelial aggregates (RNEAs) of the skin 5 is another condition that shows similar morphology to ESN and needs to be considered in the differential diagnosis. This entity is characterized by the presence of 1 or 2 nerve bundles surrounded by a sheath of bland non-keratinising squamous epithelium in a fibroinflammatory background. Two of the 5 cases described occurred in reexcision specimens similar to the RPI lesion reported by Stern and Haupt [11]. However, the remaining 3 cases had no previous history of excision or local trauma and the background showed folliculitis in one case and early nodular prurigo in the remaining 2 cases. RNEAs can be differentiated from ESN by the following features: RNEAs occurred in the face and neck whereas ESN is seen in the back. Only 1 or 2 neuroepithelial aggregates are seen in RNEAs, whereas in ESN multiple neuroepithelial structures are noted. Enlargement of nerves was seen in one case only of RNEAs, while it is a consistent finding in ESN.

The histogenesis of ESN is still unclear. Kutzner hypothesised that the squamous epithelium is arising as a result of metaplasia of perineurium provoked by adjacent inflammation [14]. At least 2 factors stand against this explanation: First, epithelial cysts with no associated thickened nerves were seen in the central part of some cases. Second, there is no EMA positive transition from the perineureal cells to the squamous epithelium [10]. Another alternative hypothesis is the derivation from pleuripotential neural crest cells which is also believed to be the histogenesis hypothesis of glandular schwannoma; a lesion characterised by the presence of true glandular tissue (Cam 5.2 positive) within a schwannoma [15]. The last suggestion is that the neuroepithelial structures may represent a hamartomatous lesion. This was dismissed BY Requena and colleagues 10 on the bases of the late age of presentation of ESN. However, hamartomas do not necessarily develop at birth and there are many hamartomatous conditions which may present at a very old age [16,17].

Another suggestion was that it may represent entrapped hyperplastic infundibular epithelium in association with hyperplastic nerve bundles. The hyperplasia is thought to be induced by various cytokines produced as a consequence to an ongoing inflammatory process resulting from external stimuli such as rubbing [18]. Indeed, experimental removal of the stratum corneum of pig’s skin by repetitive tape stripping resulted in hypertrophy of cutaneous nerves [19]. Moreover, co-culture of rat sensory neurons with injured human skin stimulated higher growth of nerves compared to those co-cultured with normal human skin [20]. We support this hypothesis and we think that a local change in the microenvironment resulting from a low-grade inflammatory reaction may induce alterations in the local anatomy accompanied by hyperplasia of both nerves and infundibular epithelium. The close association of ESN to hair follicles and the formation of squamous eddies in the epithelial sheath were considered to be supporting evidence for this hypothesis [18].

In this report, we presented another case of ESN. The exact histogenesis is not yet established and more cases are needed for detailed studies. This extremely rare condition should be considered in the differential diagnosis of perineural invasion by malignant squamous neoplasms. Both dermatologists and pathologists need to be aware of this entity to avoid misdiagnosis of malignancy.

Epithelial sheath neuroma (ESN) is a rare, benign cutaneous lesion that can histologically mimic perineural invasion typically seen in malignant epithelial tumors. Accurate recognition of this entity is crucial to prevent misdiagnosis and avoid unnecessary aggressive treatment. The absence of cytologic atypia, lack of connection to the epidermis or adnexal structures, and the clinical context should guide the diagnosis. Although its exact pathogenesis remains uncertain, increasing awareness of ESN among dermatologists and pathologists is essential. Further case reports and studies are needed to better understand its origin, behavior, and clinical significance.