An encapsulation of palisaded encapsulated neuromas

By Warren R. Heymann, MD, FAAD
Jan. 22, 2025
Vol. 7, No. 3

You know the drill — a patient presents with a solitary, slowly enlarging, dome-shaped, non-pigmented painless facial papule and asks, “Is it skin cancer?” Your clinical and dermoscopic examinations are not definitive, so you respond with uncertainty, saying, “It’s probably a benign lesion like an intradermal nevus, fibrous papule, or cyst, but it could be a basal cell carcinoma — with your permission, I recommend performing a shave biopsy.” Your anxious patient agrees and immediately wants to know what you think post-procedure. “That’s why we did the biopsy — to find out. I won’t keep the results a secret — when I know, you’ll know.” Once in a while, you can make an educated guess. If you experience the “Jack-in-the-Box” sign — the sudden popping out of neural tissue when the papule is shaved — you can be confident that the lesion is a palisaded encapsulated neuroma (PEN). (1) The romance of that “aha” moment enables reassuring the patient that all will be well. PENs were described over 50 years ago in the seminal article by Reed et al. detailing 44 cases. (2)

PENs are also called solitary circumscribed neuromas (SCNs) because many lesions are not fully encapsulated. (3) PENs are characteristically observed on the head and neck as single, asymptomatic nodules or papules with the same color as the surrounding skin. Lesions tend to involve the face (in more than 90% of the reported cases), most commonly on the nose and cheeks. PENs have been reported in the oral cavity and on the penis, eyelid, and trunk. (4,5,6)

Dermoscopy is not specific, demonstrating symmetrical, dome-shaped papules with arborizing blood vessels. A white, ivory color may also be appreciated. Reflectance confocal microscopy (RCM) images reveal a honeycomb pattern replete with follicular openings and slight papillary dermal fibrosis. Horizontally oriented blood vessels, vellus hair follicles, and prominent vellus hair bulbs are noted. These features are presumably due to pressure from the underlying tumor. (7,8)

Beutler and Cohen accurately describe the histological feature of PENs: “Histologically, a palisaded encapsulated neuroma is characterized by a network of interweaving fascicles of benign-appearing spindle cells in the papillary dermis. Nuclear pleomorphism and mitoses are typically absent. The overlying epidermis is normal. The histologic features of palisaded encapsulated neuromas may mimic those of other cutaneous neural tumors and smooth muscle tumors, including leiomyoma, neurofibroma, schwannoma, and traumatic neuroma; therefore, immunohistochemical studies may sometimes be required in order to distinguish palisaded encapsulated neuroma from similar-appearing lesions. Spindle cells within palisaded encapsulated neuromas are S-100 positive and glial fibrillary acidic protein (GFAP) negative. Factor XIIIa-positive cells are also frequently present. There is epithelial membrane antigen (EMA) staining of the capsule but not of the spindle cells. Although positive collagen IV staining is common among most cutaneous neural neoplasms, neurofibromas may occasionally be collagen IV negative; therefore, collagen IV staining can sometimes be used to differentiate palisaded encapsulated neuroma from neurofibroma.” (6)

A histopathological review of 30 cases demonstrated the following patterns: 18 lobular, 9 plexiform, 2 fungating, and one multilobular. Although most cases were well-circumscribed, capsular integrity was at least focally disrupted (73%). A Verocay body was noted only in 6 cases (20%). Importantly, Lebleblici et al. assert, “Although these morphological variants are not different in terms of clinical or biological behavior, it is important to beware of these variants, especially the plexiform pattern of SCN/PEN can be mistaken for plexiform schwannoma or plexiform neurofibroma.” (3)

The solitary PEN is a straightforward affair — where confusion and speculation reign (in my opinion) is with multiple PENs. In the original report, Reed et al. noted the histologic similarity between PENs and the neuromas of the multiple mucosal neuroma syndrome (Multiple Endocrine Neoplasia, Type 2B, MEN 2B), considering the relationship akin to that of a solitary neurofibroma versus neurofibromatosis. (2) Guo-Yan et al. reported two adult siblings (a 56-year-old man and his 50-year-old sister) who developed multiple PENs as adults with no systemic features. Unfortunately, DNA analysis for the RET proto-oncogene and PTEN gene was not performed. (9) Patients with early-onset (age 2 to 6 years) acral PENs may have Cowden syndrome (CS), an example being a 12-year-old girl with multiple lesions on the volar surfaces of her hands and feet. Her father had a known diagnosis of CS; they both shared the same PTEN mutation. (10) A report of a healthy 7-year-old girl with PENs on her nose and both feet tested negative for the RET proto-oncogene. (11) Zosteriform PENs have been reported. (12,13). As with all zosteriform neoplasms, the question of somatic mosaicism is raised — to the best of my knowledge, this has not been studied.

The etiology of PENs is obscure, being most often attributed to minor trauma. (3) This may be true sometimes, but there must be more to the story. A genetic predisposition, with rare exceptions, has not been defined. Regardless, for classical solitary lesions and most patients with multiple PENs, reassurance of their benignancy and lack of association with other systemic problems is all that is necessary. Screening for CS and MEN type 2B (a detailed family history, physical examination, and genetic analysis) is warranted for children presenting with multiple, often acral lesions.

Point to Remember: Palisaded encapsulated neuromas may present as solitary or multiple lesions. Dermatologists will recognize them by the “Jack-in-the-Box” sign as the lesions pop out during a shave biopsy. Multiple lesions presenting in childhood warrant consideration of Cowden syndrome and Multiple Endocrine Neoplasia Type 2B.

Our expert’s viewpoint

Kiran Motaparthi, MD, FAAD
Clinical Professor
Vice Chair of Education
Department of Dermatology
University of Florida College of Medicine

As Dr. Heymann points out, the “Jack-in-the-Box” sign provides a distinctive feature to an otherwise clinically nondescript lesion and permits prompt identification of PEN. (1)

Similarly, a few histopathologic clues quickly distinguish PEN from mimics, particularly from other benign neural tumors. Although encapsulation is variable, PEN constantly demonstrates separation from the adjacent dermis by an edematous stroma. Additionally, cleft-like spaces between the fascicles are also uniformly present in PEN. Even in partial biopsies, these features allow rapid differentiation from neurofibroma and schwannoma. These clues should also be applied to less common histopathologic variants, such as plexiform PEN, which can seem difficult to classify otherwise. (3) While diagnosis of PEN is made more straightforward based on these clinical and histopathologic clues, classification of patients with multiple PENs is more challenging, particularly when extracutaneous findings are absent. Similar to other authors, we recently encountered siblings with multiple, grouped PENs but without any syndromic features of Cowden syndrome or MENIII (MEN2b). (9)

1. Hsu S, Lee JB, Motaparthi K. The Jack-in-the-Box Sign: A Diagnostic Sign for Palisaded Encapsulated Neuroma. Skinmed. 2022 Aug 31;20(4):302. PMID: 35976022.

2. Reed RJ, Fine RM, Meltzer HD. Palisaded, encapsulated neuromas of the skin. Arch Dermatol. 1972 Dec;106(6):865-70. PMID: 4639250.

3. Leblebici C, Savli TC, Yeni B, Cin M, Aksu AEK. Palisaded Encapsulated (Solitary Circumscribed) Neuroma: A Review of 30 Cases. Int J Surg Pathol. 2019 Aug;27(5):506-514. doi: 10.1177/1066896919833172. Epub 2019 Mar 5. PMID: 30834800.

4. Pourshahidi S, Aminishakib P, Aliyari N, HafeziMotlagh K. Oral palisaded encapsulated neuroma; a diagnosis seldom suspected clinically. Clin Case Rep. 2023 Nov 16;11(11):e8212. doi: 10.1002/ccr3.8212. PMID: 38028074; PMCID: PMC10654556.

5. Moritz EN, Giacometti JN. Palisading Encapsulated Neuroma of the Eyelid. JAMA Ophthalmol. 2022 Feb 1;140(2):e214790. doi: 10.1001/jamaophthalmol.2021.4790. Epub 2022 Feb 17. PMID: 35175297.

6. Beutler B, Cohen PR. Palisaded Encapsulated Neuroma of the Trunk: A Case Report and Review of Palisaded Encapsulated Neuroma. Cureus. 2016 Aug 8;8(8):e726. doi: 10.7759/cureus.726. PMID: 27630799; PMCID: PMC5016044.

7. Moyano EG, Blanca MA, Pilar LM, Martos AO, Fernandez Ballesteros MD, Trelles AS. Homogeneous white patch in dermoscopy of solitary circumscribed neuroma. J Am Acad Dermatol. 2017 Feb;76(2S1):S84-S85. doi: 10.1016/j.jaad.2015.11.020. PMID: 28087044.

8. Konisky H, Huho H, Suvarnakar A, Krishna S, Huho A. Dermoscopic and reflectance confocal microscopy findings in palisaded encapsulated neuroma (PEN): report of two histologically confirmed cases. Oxf Med Case Reports. 2024 Feb 16;2024(2):omae003. doi: 10.1093/omcr/omae003. PMID: 38370506; PMCID: PMC10873705.

9. Liu GY, Song H, Xu XL. Multiple palisaded encapsulated neuromas in siblings: A case report and review of the published work. J Dermatol. 2016 May;43(5):560-3. doi: 10.1111/1346-8138.13154. Epub 2015 Oct 13. PMID: 26460241.

10. Harris E, Mir A. Acral Plexiform Palisaded Encapsulated Neuromas as the Initial Cutaneous Manifestation of Cowden Syndrome. Pediatr Dermatol. 2017 Jul;34(4):e219-e220. doi: 10.1111/pde.13161. Epub 2017 May 23. PMID: 28543709.

11. Moore RL, White CR. Multiple palisaded encapsulated neuromas in a child without other associated abnormalities. J Am Acad Dermatol. 2010 Feb;62(2):358-9. doi: 10.1016/j.jaad.2009.01.036. PMID: 20115963.\

12. Lee MS, Lee JD, Cho SH, Kim HS. Palisaded Encapsulated Neuroma in a Zosteriform Distribution. Indian J Dermatol. 2016 Jan-Feb;61(1):126. doi: 10.4103/0019-5154.174173. PMID: 26955159; PMCID: PMC4763676.

13. Bhat NN, Bhat YJ. Dermoscopic Clues in Diagnosis of Zosteriform Palisaded Encapsulated Neuroma. Indian Dermatol Online J. 2023 May 25;14(4):578-579. doi: 10.4103/idoj.idoj_413_22. PMID: 37521230; PMCID: PMC10373817.

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