Reexcision Perineural Invasion and Epithelial Sheath Neuroma Possibly on a Spectrum of Postinjury Reactive Hyperplasia Mediated by IL-6

Abstract

Epithelial sheath neuroma is a rarely recognized but established entity in the medical literature. First described in 2000 by Requena et al, there have only been 7 published cases to date, mostly in female patients and presenting as symptomatic solitary lesions on the back without a known history of trauma. In 2006, Beer et al described and reviewed a dozen cases in which epithelial sheath neuroma-like features were seen in the advent of a surgical procedure, which was termed "re-excision perineural invasion" and attributed to possible eccrine duct implantation during surgery. Our case is a 66-year-old male patient who underwent an excision of a melanocytic neoplasm in which a reactive epithelial sheath neuroma was incidentally discovered in the excision specimen, adjacent to the biopsy site cicatrix. Histologically, there was benign cutaneous nerve hyperplasia with a proliferation of squamous epithelium in intimate apposition to the nerve bundles in the superficial dermis. We postulate that the process active in the formation of re-excision perineural invasion is the same as in epithelial sheath neuroma and that minor trauma not appreciable on histologic examination is responsible in the latter entity. We performed IL-6 staining and documented that IL-6 was upregulated at the interface of the nerve and reactive epithelium, but was absent in nerves distant from the site of surgery, suggesting that IL-6 may be essential to the lesion's development. The recognition of reactive epithelial sheath neuroma including the subcategory of re-excision perineural invasion is crucial for the dermatopathologist to prevent mislabeling this reactive entity as a perineural squamous cell carcinoma, which has clinical consequences for the patient such as wider re-excision and radiation treatment. Additionally, we have identified a potential pathophysiologic basis for this lesion.

Epithelial sheath neuroma with extension to the subcutis

“…[1][2][3][4][5][6] We report the first case of ESN to extend down to the subcutis, demonstrating that not all cases of ESN are confined to be associated with dermal cysts, and some have theorized that traumatic implantation could play a role in some or all cases of ESN. 7,8 Of note, the histological features in our case, with no reactive changes in the subcutis around the ESN residuum, argue against traumatic implantation via shave biopsy as the cause of subcutaneous involvement.…”

“…Scattered lymphocytes and/or plasma cells have also been described in ESN. The differential diagnoses of greatest practical importance are perineural invasion of an invasive well differentiated squamous cell carcinoma, as well as pseudo‐perineural invasion sometimes seen at surgical sites . A traumatic neuroma with entrapped epithelial structures is also a consideration.…”

“…If ESN is indeed a reactive process, the underlying pathogenesis may be related to rubbing or an alternative external stimulus leading to an inflammatory response inducing various cytokines which ultimately lead to nerve hyperplasia . In addition, the reactive enlarged nerves may be stimulating keratinocyte proliferation around them via the release of interleukin‐6 …”

“…The differential diagnoses of greatest practical importance are perineural invasion of an invasive well differentiated squamous cell carcinoma, as well as pseudo-perineural invasion sometimes seen at surgical sites. 7 A traumatic neuroma with entrapped epithelial structures is also a consideration. The lack of scar, presence of enlarged nerve fibers in the superficial dermis, and clinical history make ESN a unique entity.…”

Epithelial sheath neuroma: A case series

“…9 Dunn et al 10 also proposed in their report that the lesion may arise from neural crest remnants after embryonal development that differentiate into neural and squamous epithelial elements. Wang et al 11 suggested that ESN may arise from localized inflammation or minor trauma that induces the production of interleukin-6emediated hyperplasia.…”