Are You Confident of the Diagnosis?

Neuromas are proliferations of the basic units of peripheral nerves, axons and their surrounding Schwann cells, in roughly equal ratios. There are two major subtypes: palisaded encapsulated neuroma (PEN) also known as solitary circumscribed neuroma, characterized by hamartomatous proliferations of nerve fibers without previous trauma; and traumatic neuroma, also known as amputation neuroma, characterized by regenerative proliferations of nerve fibers secondary to traumatic injury to nerves.

What you should be alert for in the history

PEN is a benign neural skin tumor, first described in 1972 by Reed et al. It has characteristic clinical, histopathologic, and immunohistochemical findings that have been well described. Patients usually present with a solitary, slowly enlarging, firm painless papule, most often located on the face. They tend to be of several years duration. Less than 10% occured in sites other than the face. Other sites reported rarely included the trunk, arms, oral cavity, eyelids, glans penis, and acral sites. Patients usually deny any history of similar previous lesions. There is often no history of previous trauma at the site of the lesion.

Characteristic features on physical examination

Characteristic features include a 2-6 mm, solitary (rarely multiple), firm, pink or flesh-colored papule, commonly located on the face near mucocutaneous junctions, but also found on the runk, arms, oral mucosa, eyelids, glans penis, and acral sites. There have been case reports of multiple PENs occurring in these locations. Overlying skin markings are lost. Telangiectasia is minimal or absent. Ulceration is present only after local trauma (ie, shaving).

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Expected results of diagnostic studies

Clinical differential diagnoses include:

Basal cell carcinoma–PEN can be differentiated from BCC by longer duration of tumor, few telangiectasias, lack of ulceration, and defined borders

  • Intradermal melanocytic nevus–Nevi tend to be less firm than PEN to palpation, and they retain normal skin markings helping to differentiate the two entities

  • Epidermal cysts

  • Skin appendage tumors (an example being an eccrine spiradenoma amongst others)–PEN and skin appendage tumors are difficult, if not impossible, to differentiate clinically

Histological features of PEN include a solitary well-circumscribed, partially encapsulated, intradermal nodule composed of interdigitating spindle cells grouped in distinct fascicles (Figure 1, Figure 2). Fascicles are often separated from one another by artifactual clefts. Tumor cells show an eosinophilic cytoplasm, and pointed, wavy nuclei. Nuclear pleomorphism and mitotic activity are rarely seen. Fibrosis and inflammation are not usually evident, helping to distinguish PEN. from traumatic neuroma. Occasionally, a small nerve may be located at the periphery of the nodule, and can be traced into the tumor, with its perineurium merging with the capsule of the PEN. A nodular growth pattern is most frequently seen, but other patterns reported include epithelioid, plexiform, and multinodular

Figure 1.

Low-power view of PEN.

Figure 2.

High-power view PEN.

Immmunohistochemistry can help differentiate PEN from other entities. Characteristically, PEN shows:

— (+) S-100 protein, collagen Type IV staining of the tumor cells, indicating Schwann cell differentiation

–(+) Epithelial Membrane Antigen (EMA) staining of the incomplete or complete capsule, indicating its perineural origin

–(+) Neurofilament staining within spindle cell fascicles, indicating presence of axonsClinical differential diagnoses include:

Basal cell carcinoma–PEN can be differentiated from BCC by longer duration of tumor, few telangiectasias, lack of ulceration, and defined borders

Intradermal melanocytic nevus–Nevi tend to be less firm than PEN to palpation, and they retain normal skin markings helping to differentiate the two entities

Epidermal cysts

Skin appendage tumors (an example being an eccrine spiradenoma amongst others)–PEN and skin appendage tumors are difficult, if not impossible, to differentiate clinically

Diagnosis confirmation

Clinical differential diagnoses include:

–Basal cell carcinoma. PEN can be differentiated from BCC by longer duration of tumor, few telangiectasias, lack of ulceration, and defined borders.

–Intradermal melanocytic nevus. Nevi tend to be less firm than PEN to palpation, and they retain normal skin markings helping to differentiate the two entities.

–Epidermal cysts.

–Skin appendage tumors (an example being an eccrine spiradenoma amongst others). PEN and skin appendage tumors are difficult, if not impossible, to differentiate clinically.

Histopathologic differential diagnoses include

–Traumatic neuroma. Similar to PEN, containing both Schwann cells and axons, but inflammatory cells, foreign body reaction, and scarring are also evident

–Schwannoma. Usually located deeper in dermis and in subcutaneous tissue; they lack axons; they contain Antoni A&B tissue with Verocay bodies

–Neurofibroma. Unlike PEN, they lack a capsule, have many less ensheathed axons, and contain a mucopolysaccharice ground substance

–Leiomyoma. Distinguished from PEN by a smooth muscle cell component wtih fasclicles of spindle cells with cigar shaped nuclei and pink cytoplasm, and characteristic immunostaining including positivity for the smooth muscle markers actin and desmin

Traumatic Neuromas

What you should be alert for in the history

Traumatic neuromas are uncommon tumors that develop in locations of injured peripheral nerves. Suspicion should be raised in cases with a history of a painful papule or nodule at a site of former injury.

Characteristic features on physical examination

They usually present as a painful nodule, most often on the palm. They have been reported at other sites of trauma including surgical scars, amputation stumps, subungal locations, penis, oral cavity, and head and neck locations usually after surgery. Clinically, they are usually between 0.5 to 2.0 cm, and appear as skin-colored, firm papules or nodules. Unlike PEN, they tend to be symptomatic, and are associated with tingling, itching, and electricity-like pain.

Diagnosis confirmation

Clinical differential diagnoses for traumatic neuroma include:

–Hypertrophic scar



–Rudimentary supernumerary digit is considered a variant of a traumatic neuroma

Hisological differential diagnoses for traumatic neuroma include:

–Hypertrophic scar

–Acral fibrokeratoma




Who is at Risk for Developing this Disease?

PENS tend to occur in adults. Various case series quote ages ranging from 40 to 60 years old. Men and women tend to be equally affected. There are few case reports of children who have been diagnosed with PEN histologically. Several case reports of PEN in children have involved multiple lesions in acral locations. Solitary PEN usually occurs sporadically, and there is not usually a history of trauma preceding the lesions.

Traumatic neuromas can occur at any age and in both sexes. They are more common in people in professions with a higher risk of physical injury. Surgery with damage to peripheral nerves, tooth extraction, and amputation injuries are other known risk factors for traumatic neuromas.

What is the Cause of the Disease?

Some authors view PEN as a reactive, hyperplastic process related to traumatic neuromas. However, in many case series, there is no history of antecedant trauma in the location of tumor development. Also, the general absence of histologic changes suggestive of trauma such as scar and inflammation point against the theory of a traumatic origin. PEN most likely represents a hamartomatous overgrowth of axons and their surrounding Schwann cells in a duplication of the normal 1:1 ratio between these two peripheral nerve components. The etiology of this overgrowth remains unknown, and continues to be a matter of debate. Thus far, a definite traumatic origin has not been established.

Atraumatic neuroma


Any damage to peripheral nerve fibers can lead to development of atraumatic neuroma. Traumatic neuromas are often encountered after injury to peripheral somatic, autonomic and cranial nerves. In traumatic neuroma, a solitary mass of regenerating axons and Schwann cells develops at the proximal end of a nerve stump after nerve transection. Amputation neuroma is the most common form.


After a nerve has been transected, the distal segments of the nerve fibers degenerate, whereas the more proximal segments regenerate and attempt to reconnect with the distal segment of the transected nerve. Frequently, this attempt is unsuccessful, and the regenerating proximal segments form a mass of tangled nerve fascicles that often become incorporated into fibrotic scar tissue. This leads to the classic clinical presentation of a painful nodule at the site of previous trauma.

Systemic Implications and Complications

A correct histological diagnosis is extremely important in this tumor, because they are BENIGN and RARELY RECUR after treatment. Misdiagnosis as a neurofibroma, schwannoma, or mucosal neuroma would likely lead to unnecessary clinical concern and further patient testing. Unlike these tumors, PEN lacks the implications for underlying systemic disease or malignancy. Below is a discussion of several entities in the clinical and histological differential diagnosis of PEN that do have associations with systemic disease.

Distinguishing PEN from a plexiform neurofibroma can be difficult histologically. A correct pathological diagnosis is important because neurofibromas can be associated with Neurofibromatosis Type I (von Recklinghausen’s disease), a disease with potentially serious implications for internal neurofibromas of the peripheral and central nervous system, systemic disease, and the potential for malignancy in the form of neurofibrosarcoma. There is no association of PEN with neurofibromatosis.

The presence of multiple schwannomas of the skin may be indicative of neurofibromatosis type 2 (NF2), or schwannomatosis, which is associated with mutations in the NF2 gene. NF2 patients can have vestibular schwannomas, meningiomas, and various ocular abnormalities.

Multiple mucosal neuromas are considered pathognomonic for multiple endocrine neoplasia, type 2b (MEN 2b). Nearly all patients with this syndrome demonstrate multiple mucosal neuromas. MEN 2b is inherited in an autosomal dominant fashion, although half of cases are sporadic. The syndrome is a constellation of mulitple mucosal neuromas, medullary thyroid carcinoma, and pheochromocytoma. Patients may be described as having a Marfanoid body habitus and gastrointestinal ganglioneuromatosis. Mucosal neuromas are an early feature of this syndrome, often occurring at birth, and are often the presenting feature allowing the diagnosis to be made.

Cutaneous meuromas are unusal in this syndrome. Reed, who originially described PEN, suggested that PEN may mimic the mucosal neuromas of MEN 2b. There is little evidence to support this. To date, there is no well-established link to any neurocutaneous or inherited endocrine neoplasia syndrome and PEN. A solitary cutaneous tumor, with histologic features of PEN, should therefore not prompt an exhaustive work-up for the above entities in the absence of other associated stigmata.

Treatment Options

There are no consensus guidelines on the treatment of either PEN or traumatic neuroma.

Surgical excision is considered curative for PEN, although it is a benign lesion. Location, age of patient, and potential morbidity following a surgical excision should be considered and discussed with patient prior to operating. No medical therapies are effective.

The usual treatment for PEN is conservative surgical excision, which is considered curative. Occasionally, the initial biopsy removes the entire tumor and further excision may not be necessary. Very few cases of recurrence after conservative excision following biopsy have been reported. All of these were local recurrences, and were completely removed with no subsequent recurrence upon re-excision.

In the original case series of PEN, it was noted that when the lesion is cut into during the process of excision, the epidermis and superficial dermis separate cleanly, exposing a ball of tumor nestling in the dermis. This nodule was reported to shell out cleanly and intact as a white sphere. This finding can help narrow the differential diagnosis since few other cutaneous tumors do this, pilar cyst being the other notable entity. In the case of PEN, patients should be reassured that excision is considered curative and there is a low probability of recurrence, which mitigates the need for further testing or concern for systemic disease or malignancy.

Traumatic Neuroma

Surgical excision is indicated for traumatic neuroma, primarily for symptomatic control of pain. Attempts should be made to reposition the proximal nerve stump into a scar-free area such as within a muscle flap. Adjunctive intralesional kenalog at doses starting at 10 mg/cc have been used prior to or following surgical repositioning of the nerve ending. This could be titrated up to clinical response (ie, decrease in pain symptoms).

Because of the neurologic component of traumatic neuromas, management is complex, and should involve surgical specialties such as orthopedic hand surgery, or ENT surgery depending on tumor location. Once a tissue diagnosis is confirmed via biopsy, an MRI is often useful to delineate the extent of tissue involvement. Current surgical modalities include extensive neurectomy, flap repairs, and subsequent steroid injections.

Optimal Therapeutic Approach for this Disease

The approach to these patients is surgical (see the treatment options sections for details), as no medical therapies are effective

Patient Management

In the majority of cases, no long-term managment is necessary, as these are benign conditions without systemic implications that would require long-term monitoring. Patients and their families need to be reassured that these are not related to other syndromes such as MEN 2b or neurofibromatosis.

Unusual Clinical Scenarios to Consider in Patient Management

PEN is a benign tumor that most often affects middle-aged adults and both sexes equally. It is usually a solitary lesion most often located on the face. Unusual clinical scenarios to consider include:

–Multiple tumors

–Tumors located in unusual locations: oral mucosa, genitalia, acral sites

–Tumors occuring in children

The clinical diagnosis of PEN is quite challenging. Diagnosis is usually made on characteristic histologic and immunohistochemical studies. It should be kept in the clinical and histologic differential for slow growing, asymptomatic, firm, dome-shaped papules located on the skin.

What is the Evidence?

Reed, RJ, Fine, RM, Meltzer, HD. “Palisaded, encapsulated neuromas of the skin”. Arch Dermatol. vol. 106. 1972. pp. 865-70. (This is the originial description of PEN as a clinical and histopathologic entity. It was a review of 44 cases of a distinctive, encapsulated neuroma.)

Dover, JS, From, L, Lewis, A. “Palisaded encapsulated neuromas. A clinicopathologic study”. Arch Dermatol. vol. 125. 1989. pp. 386-89. (This is a case series of 81 cases that were studied after the original description by Reed et al. The authors describe similar clinical findings and histopathology as reported by Reed. The authors introduce the concept of minor trauma and subsequent nerve regeneration as an etiology of PEN.)

Jokinen, CH, Ragsdale, BD, Argenyi, ZB. “Expanding the clinicopathologic spectrum of palisaded encapsulated neuroma”. J Cutan Pathol. vol. 37. 2010. pp. 43-8. (The authors present three cases of clinically and histopathologically unusual PEN including those on acral sites, a case of plexiform histology, and a case that involved multiple lesions. The authors also emphasize that no well-established link to systemic syndromes has been made with PEN.)

Newman, MD, Milgraum, S. “Palisaded Encapsulated Neuroma (PEN): An often misdiagnosed neural tumor”. Dermatology Online Journal. vol. 14. 2008. -12. (The authors report a case of a young man with Fragile X syndrome and PEN. They do not feel PEN is part of Fragile X syndrome. They also echo other studies that state PEN lacks associations with underlying systemic disease.)

Argenyi, ZB, Bolognia, JL, Jorizzo, JL, Rapini, RP. “Neural and neuroendocrine neoplasms (other than neurofibromatosis)”. Dermatology. vol. 115. 2008. pp. 1795-1811. (A well-known textbook of dermatology used by practicing physicians, residents, and medical students worldwide.)

Fletcher, CDM. “Solitary circumscribed neuroma of the skin (so-called palisaded, encapsulated neuroma). A clinicopathologic and immunohistochemical study”. Am J Surg Pathol. vol. 13. 1989. pp. 574-80. (A review of 39 cases from London, England with typical clinicopathologic and immunohistochemistry for PEN. This manuscript was published at approximately the same time as the case series by Dover et al. findings among both reviews are similar, however, Fletcher et al were able to identify the nerve of origin for several cases of PEN while Dover et al were not. Also, Fletcher does not feel there is enough evidence to suggest a traumatic etiology.)

Argenyi, ZB, Cooper, PH, Santa Cruz, D. “Plexiform and other unusual variants of palisaded encapsulated neuroma”. J Cutan Pathol. vol. 20. 1993. pp. 34-39. (A review of 55 cases of PEN that showed growth patterns different from the usual solitary nodular form. The authors also attempt to make a correlation between minor trauma such as acne lesions on the face and the development of PEN. They do not discount the association.)

Rashid, RM, RM, Rashid, Thomas, V. “Subungal traumatic neuroma”. J Am Acad Dermatol. vol. 63. 2010. pp. e7-e8. (A letter to the editior describing a rare case of subungal traumatic neuroma that, according to the authors, had not previously been described. The authors highlight the small amount of information available concerning the most effective management strategies for traumatic neuroma.)

Argenyi, ZB, Santa Cruz, D, Bromley, C. “Comparitive light microscopic and immunohistochemical study of traumatic and palisaded encapsulated neuromas of the skin”. Am J Cutan Dermatopathol. vol. 14. 1992. pp. 504-10. (This review highlights the substantial histopathologic differences that exist when comparing traumatic neuroma and PEN.)

Koutlas, IG, Scheithauer. “Palisaded encapsulated (“solitary circumscribed”) neuroma of the oral cavity: a review of 55 cases”. Head Neck Pathol. vol. 4. 2010. pp. 15-26. (A case series that reviews 55 cases of oral PEN/SCN that is frequently found in the mouth per this report. The authors also suggest the finding that most PEN have a GFAP negative immunoreaction, which may be of use in distinguishing this entity from other peripheral nerve sheath tumors.)