Traumatic Neuroma With Melanoma Perineural Invasion.

Traumatic neuroma is a reactive non-neoplastic neural proliferation that results from trauma. Although such type of lesions found surgical scars due to different reasons, its involvement by residual or recurrent malignancies is rarely reported. In this article, we describe an unusual case of traumatic neuroma with perineural invasion by invasive melanoma.

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

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.

Palisaded encapsulated neuroma: an entity to consider in the differential diagnosis of the eyelid nodule. A case report.

A 58-year-old female presented to her ophthalmologist with a firm 5 mm × 5 mm painless nodule on her right eyelid that had been present for 4 years. The nodule was well encapsulated and was composed of spindled cells. The central portion of the tumor contained a neuroid cell population with tapered ends. The periphery of the neuroid cell population exhibited a palisading pattern. Myxoid stromal changes could be appreciated between the neuroid cell population and the capsule. Routine hematoxylin-eosin staining and S100, epithelial membrane antigen, and neurofilament were used to diagnose the nodule as palisaded and encapsulated neuroma, a benign peripheral nerve sheath tumor derived from Schwann cells.

[Morphologic features of reticular (retiform) perineuroma].

The report deals with 8 cases of reticular (retiform) perineuroma, a rare soft-tissue variant of the latter. It presents as a lace-like pattern of long cytoplasmic outgrowths of tumor cell clusters in myxoid or tender collagenized stroma. Despite its potential for infiltrative growth, perineuroma has a benign clinical course.

Intramedullary amputation neuromas associated with spinal ependymomas.

We report 5 spinal intramedullary masses containing combined ependymoma and traumatic neuroma. The ependymomas, grade II "cellular" types, were intermixed with or separate from wavy, vaguely fascicular tissue that contained multiple axons immunoreactive for neurofilament protein. The neuromas presumably arose from small perivascular nerve twigs that have been implicated in the pathogenesis of intramedullary neuromas in non-neoplastic spinal diseases. Pathologists should be aware of this distinctive intramedullary tissue that is not to be confused with a neoplasm.

Mucosal Schwann cell "hamartoma": clinicopathologic study of 26 neural colorectal polyps distinct from neurofibromas and mucosal neuromas.

Colorectal polyps containing S-100-positive neural proliferations in the lamina propria that lack ganglion cells have been variously referred to as "neuromas" or "neurofibromas." However, these lesions have not been systematically examined, and whether they are associated with type 1 neurofibromatosis (NF1) or other inherited syndromes is unknown. The aim of this study was to evaluate the clinicopathologic and immunohistochemical features of these lesions, in comparison to colorectal neurofibromas from known NF1 patients. Morphologically similar lesions from 26 patients (mean age, 62 y; range, 46 to 88 y; male/female ratio, 10/16) were retrieved from surgical pathology and consult files. Clinical and endoscopic data were obtained, and immunohistochemistry for S-100 protein, glial fibrillary acidic protein, neurofilament protein (NFP), epithelial membrane antigen, claudin-1, CD34, smooth muscle actin, and KIT was performed. The findings were compared with those in mucosal biopsies of 5 submucosal neurofibromas from NF1 patients. All 26 polyps were sessile, ranging from 1 to 6 mm in size (mean, 2.5 mm). Most arose in the distal colon (15 rectosigmoid, 7 descending, 2 transverse, and 2 ascending), and were incidentally found at screening colonoscopy. After a mean follow-up of 6.5 years (range, 3 mo to 17.5 y), none of the patients developed other neural polyps, and none had evidence of NF1 or other inherited syndromes. Histologically, the lamina propria of the polyps contained a diffuse cellular proliferation of uniform bland spindle cells with elongated, tapering nuclei, abundant, dense eosinophilic cytoplasm, and indistinct cell borders, entrapping adjacent crypts. No nuclear atypia, pleomorphism, mitotic activity, or associated ganglion cells were observed. All showed strong staining for S-100 protein in essentially 100% of cells. NFP highlighted rare axons in 7 lesions. All other markers were negative. The 5 neurofibromas showed similar histologic features, but were generally less uniformly cellular, showed some intralesional heterogeneity, and showed less extensive staining for S-100 protein; all contained scattered NFP-positive axons. In summary, solitary colorectal polyps containing pure Schwann cell proliferations in the lamina propria are not associated with NF1. Distinguishing these lesions from NF1-associated neurofibromas is difficult based on histologic features; the presence of an underlying submucosal nodule or mass should be excluded endoscopically, and immunohistochemistry should be performed. Although their nature is uncertain, we propose the interim designation "mucosal Schwann cell 'hamartoma'" to avoid confusion with the neural lesions that have significant associations with inherited syndromes.

Cutaneous melanocytoneuroma: the first case of a distinctive intraneural tumor with dual nerve sheath and melanocytic differentiation.

Many melanocytic nevi contain areas similar to nerve sheath tumors (NST) and NSTs with melanin have been described. There are some NSTs with at least partial intraneural location, including neurofibromas, plexiform neurofibromas, granular cell tumors and the recently described, dendritic cell neurofibroma with pseudorosettes. We describe the case of an NST with melanocytic differentiation and intraneural location, for which we suggest the term 'melanocytoneuroma' (MCN). It arose in the skin of a 67-year-old woman with no previous history of melanoma or neurofibromatosis. The lesion presented as a papule and histologically consisted of a dermal nodule without junctional melanocytic activity. The lesion comprised an intraneural proliferation of large epithelioid eosinophilic cells with prominent cell borders imparting a 'plant-like' appearance. The cells were also seen within adjacent nerve twigs and were positive for S100, Melan-A, HMB-45, microphthalmia transcription factor and PGP 9.5. The lesion was entirely surrounded by an epithelial membrane antigen-positive-perineurial coat and the individual tumor cells were invested by laminin and collagen type-IV-positive basal lamina-like material. The lesion did not show any evidence of atypia and following complete excision, no recurrence has been documented. In conclusion, this unusual lesion represents an intraneural proliferation with melanocytic and nerve sheath cell differentiation, to which we have accorded the appellation, MCN.

Unusual benign myxoid nerve sheath lesion: myxoid palisaded encapsulated neuroma (PEN) or nerve sheath myxoma with PEN/PEN-like features?

A 38-year-old woman had a polypoid nodule on her scalp. The lesion histopathologically demonstrated an extensive myxoid lobular lesion associated with a nonmyxoid and cellular area in the peripheral area of the lesion. The features of the peripheral cellular area resembled those of palisaded encapsulated neuroma (PEN). Most of the lesion was myxoid, with a large lobule in which several thin fibrous septa were present, dividing it into smaller lobules. The myxomatous area was composed of spindle cells or stellate cells with elongated cytoplasmic processes. There was a loose cellular network with a reticular and netlike network pattern or a lamellar pattern. From the immunohistochemical findings, as well as the histopathologic features, the whole lesion was thus considered to be a PEN, whereas the main, myxoid, lobular lesion was thought to have been caused by myxoid changes within a PEN, namely, myxoid PEN. It cannot be completely ruled out, however, that this case could be that of a nerve sheath myxoma with a PEN/PEN-like lesion. Thus, the present case may suggest that PEN can show extensive myxoid change or may demonstrate a relationship between PEN and nerve sheath myxoma.

Ankyrin G and voltage gated sodium channels colocalize in human neuroma--key proteins of membrane remodeling after axonal injury.

We tested if ankyrin G could be detected in human neuroma, if it colocalized with site-specific peripheral nerve sodium channels that accumulate at axon tips of injured nerve, and if there are differences in the distribution of these proteins in non-painful neuroma and painful neuroma tissue vs. normal nerve. Frozen sections from one painful, six non-painful, and three normal nerves were immunocytochemically examined. A double labeling technique with highly specific antibodies against peripheral nerve type 1 (Na(v)1.7), and peripheral nerve type 3 (Na(v)1.8) sodium channels and anti-ankyrin G antibodies detected sodium channels and ankyrin G on the same section, using confocal laser scanning microscopy. Ankyrin G colocalized with both types of sodium channels. Neuroma specimens exhibited considerably larger immunofluorescence for both sodium channels and ankyrin G compared with normal nerve. The painful neuroma presented an even more pronounced immunolabeling in clusters. Findings support results from animal models that link ankyrin G with clustering of sodium channels at axon tips of unmyelinated, sprouting fibers. A common (repair-) mechanism that exists throughout the human nervous system for clustering sodium channels at a high density is assumed. A dysregulation in this membrane remodeling mechanism might be an initial step in a cascade that leads to a painful rather than a non-painful neuroma.

Painful neuromas: a potential role for a structural transmembrane protein, ankyrin G.

OBJECT: Severe nerve injury induces the formation of a neuroma. Some neuromas cause excruciating pain. Overexpression of Na+ channels leads to hyperexcitability and painful phenomena. Ankyrin G, a multifunctional transmembrane protein of the axolemma, might be a key protein in neuroma formation because it binds Na+ channels in the initial segments of a regenerating axon and links with neuronal cell adhesion molecules. The authors wanted to determine if ankyrin G could be detected in neuroma, and if present, whether there would be differences in distribution between nonpainful neuromas, painful neuromas, and normal nerve. METHODS: First, frozen sections of nine nerve specimens obtained from six patients (six nonpainful neuromas, one painful neuroma, and two normal nerves) were immunocytochemically screened for ankyrin G by using confocal laser scanning microscopy. Second, specimens from 29 patients (seven painful neuromas, 15 nonpainful neuromas, and seven normal nerves) were examined using immunoblot analysis for their ankyrin G content. Western blot analysis detected ankyrin G, which was visualized by applying the enhanced chemiluminescence technique. Computerized densitometry was used to quantitate ankyrin G expression by comparing band intensities. Normal nerve served as control. Neurofilament was used as a marker for nerve tissue content. Ankyrin G could be detected and was found to be increased in neuromas. The mean band intensity values were 1838 for painful neuromas, 1166 for nonpainful neuromas, and 411 for normal nerves. In two cases the authors were able to compare specimens of painful neuroma and normal nerve from the same patient. The painful neuromas exhibited considerably higher levels of ankyrin G. Painful neuroma and normal nerve densitometry values were 499 and 165, respectively, for one patient, and 4254 and 821, respectively, for the other patient. Painful neuromas were also found to have higher neurofilament values than nonpainful neuromas. CONCLUSIONS: Altered regulation of ankyrin G after nerve injury may lead to hyperexcitability and painful phenomena via clustering of Na+ channels. A propensity to overexpress ankyrin G after peripheral nerve trauma may turn out to be a factor in the development of painful neuromas and neuropathic pain. The relevant literature regarding the importance of ankyrin G for nerve regeneration and nerve membrane remodeling is reviewed.

Granular cell traumatic neuroma: a lesion occurring in mastectomy scars.

BACKGROUND: Granular cell changes can be observed in a variety of benign and malignant tumors, and are seen more commonly in granular cell tumors, which in about 5% of cases develop in the breast. Granular cells also have been observed in sites of previous trauma, such as surgery, and are found to be inflammatory reactions of histiocytic origin. METHODS AND RESULTS: We investigated, morphologically and immunohistochemically, 2 granular cell lesions occurring in mastectomy scars after surgery for carcinoma. Both lesions were composed of strands and nests of large granular cells, haphazardly set in a background of fibrous tissue, with sparse inflammatory infiltrates. Several tortuous hypertrophic nerve bundles were also embedded in the fibrous tissue. A few of these nerve bundles showed degenerative changes and contained granular cells. Immunohistochemically, granular cells were positive for S100 protein, neuron-specific enolase, vimentin, and CD68 antigen. CONCLUSIONS: We consider these proliferative lesions of peripheral nerves to have the features of both granular cell tumor and traumatic neuroma. These cases indicate that traumatic neuroma can undergo extensive granular cell changes and constitute a previously unrecognized entity, which we provisionally label granular cell traumatic neuroma. Granular cell traumatic neuroma has to be taken into consideration when evaluating lesions occurring at mastectomy scars and should be differentiated from malignant tumors with granular cells, such as apocrine carcinoma and alveolar soft part sarcoma.

Epithelial sheath neuroma: a new entity.

The authors describe four examples of a peculiar cutaneous lesion characterized histopathologically by a proliferation of enlarged nerve fibers ensheathed by squamous epithelium involving the superficial dermis. The perineural epithelial sheaths were composed of uniform squamous epithelium with evidence of cornification in the form of dyskeratotic cells or resulting in orthokeratotic basket-weave corneocytes. Immunohistochemical studies confirmed the epithelial and neural nature of the two components of the lesions, with the nerve fibers expressing immunoreactivity for S-100 protein, neurofilaments, CD57, and nerve growth factor receptor, whereas the perineural epithelial sheaths showed immunoreactivity for cytokeratins. The authors propose the term "epithelial sheath neuroma" for this lesion and believe that it is a distinct and a previously undescribed benign neoplasm of both cutaneous nerves and epithelial elements.

Fine-needle aspiration of neural lesions.

The cytomorphologic features of 13 neural lesions sampled by fine-needle aspiration (FNA) are reviewed. The frequencies at which various architectural features including Verocay bodies, filamentous background, and vascular arcades were present was recorded, along with the frequencies of cytologic findings including the presence of spindle cells, wavy nuclei, intranuclear inclusions, fishhook nuclei, nuclear pleomorphism, filamentous cytoplasm, and mitotic figures. Verocay bodies were a rare finding, present in only 1 of 11 cases. Vascular arcades were similarly infrequent (1/11 cases). Spindle-shaped cells along with wavy nuclei were the most frequent findings, with fishhook-shaped nuclei and a filamentous background of high frequency (9/11 cases). Our study indicates that some of the characteristic features recorded in the literature are rarely seen in needle aspiration smears, but features such as spindle-shaped cells, wavy and fishhook-shaped nuclei, and a filamentous background are relatively frequent findings.

Neuropeptide immunoreactivity in ligature-induced neuromas of the inferior alveolar nerve in the ferret.

Injury to branches of the trigeminal nerve can sometimes result in persistent dysaesthesia. In an attempt to understand the aetiology of this condition we are currently investigating changes which occur at the injury site. In the present study we have examined the expression of seven neuropeptides, all of which have been implicated in nociceptive transmission, or have previously been shown to have altered expression following nerve injury. In 20 adult ferrets the inferior alveolar nerve was sectioned and ligated, and recovery permitted for 3 days, 8 days, 3 weeks, 6 weeks or 12 weeks. Longitudinal sections of the neuromas were processed using immunohistochemical techniques to quantify the expression of substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide, galanin, somatostatin, enkephalin and neuropeptide Y. After 3 days, all of the neuropeptides were expressed at the injury site. In the neuromas examined after longer recovery periods these levels of expression had declined and were similar to those found in the contralateral controls. This initial high level, followed by a decline, parallels the incidence of ectopic neural activity recorded electrophysiologically in the same model. It is, therefore, possible that the accumulation of neuropeptides at the injury site may play a role in the initiation or modulation of ectopic neural activity.

Peptides and neuromas: calcitonin gene-related peptide, substance P, and mast cells in a mechanosensitive human sural neuroma.

We examined and compared a mechanosensitive human sural neuroma and a contralateral sural nerve collected simultaneously from a patient involved in a diabetic neuropathy research protocol. Using indirect immunofluorescence staining. we identified a striking difference in the content within axons of two neuropeptides, substance P (SP) and calcitonin, gene-related peptide (CGRP), between the contralateral nerve and the neuroma. Unlike the contralateral nerve, where immunofluorescence was sparse, a significant number of disorganized axon profiles that stained brightly positive for CGRP or SP were identified in the neuroma. In contrast, staining for tyrosine hydroxylase, a label of sympathetic axons, was largely absent except around one large arteriole. The neuroma specimen also contained large numbers of serotonin-containing mast cells, only noted occasionally in the contralateral nerve. The peptide staining and mast cell accumulation in the human neuroma closely resembled changes we have previously observed in an animal neuroma model. Local neuropeptides may play a role in the injury response of peripheral nerve, and may be related to mechanosensitivity.

Amputation neuroma of the hepatic hilum after orthotopic liver transplantation.

Amputation neuromas following biliary surgery have been previously reported. There are no descriptions, however, of amputation neuroma following liver transplantation. Serial hilum sections taken from 93 hepatectomy specimens obtained during the clinical course of 262 consecutive orthotopic liver transplantations revealed 26 amputation neuromas (27.9% of the specimens examined). The finding was confirmed by immunohistochemistry with numerous S-100 protein positive cells intermingled with neurofilaments interrupting the perineurial layer of cells testing positive for epithelial membrane antigen. Neuromas were found in liver specimens obtained between 89 and 775 days post-transplant (mean time, 211 days). The incidence of neuroma was higher in specimens resected more than 3 months post-transplant. There was only one symptomatic patient, who died from extrahepatic cholestasis demonstrated at autopsy to be caused by a hilar neuroma obstructing the main bile duct.

Mucosal neuromas and plexiform neurofibromas: an immunocytochemical study.

Mucosal neuromas (MN), a component of multiple endocrine neoplasia (MEN) type IIb, may be confused histologically with plexiform neurofibromas (PN), a component of neurofibromatosis. The ability to distinguish between these two markers for different genetic diseases is crucial, as the risk of development of medullary thyroid carcinoma and pheochromocytoma in affected patients with MEN IIb is great. We studied two cases each of MN and PN by immunocytochemistry (IC). Epithelial membrane antigen (EMA) proved to be the most useful marker. MN consisted of bundles of disorganized and tortuous nerve fibers surrounded by a thickened perineurium that expressed the cellular phenotype EMA(+), S-100(-). PN consisted of enlarged nerve fascicles with a loose myxoid stroma and was EMA negative. Thus, IC highlighted the differing pattern of growth and histogenesis of the proliferating cells in the two lesions and is likely to be especially useful in those lesions with atypical histology.