Cellular neurothekeoma: A tribute to Barnhill and Mihm and a remembrance of Martin C. Mihm Jr., MD
By Warren R. Heymann, MD, FAAD
Aug. 2, 2023
Vol. 5, No. 31
The profound sense of loss prompting people to endure waiting over 24 hours in a queue to pay their final respect to Queen Elizabeth II at Westminster Hall was an astonishing sight last year. The overwhelming majority of Britons had never known another monarch; her death marked the end of an era and tens of thousands were compelled to share the moment. It is disorienting to lose an icon that has been with you from the outset.
I had the honor of training in dermatopathology with the late Wallace H. Clark Jr. He was so fond of his colleague Martin C. Mihm Jr., with whom he worked on melanoma. I never met Dr. Mihm personally, although he was part of my professional life through Dr. Clark’s reminiscences, lectures, and studying his insightful articles. Dr. Mihm passed away on July 19, 2022. He was dermatopathology royalty, in deed and persona. My sense of loss parallels those of the Queen’s subjects. Please read his obituary for details on his remarkable life and contributions to dermatology. This commentary is dedicated to Dr. Mihm.
Since the term neurothekeoma (NT) was introduced in 1980 there has been ongoing confusion as the designation has persisted in the literature. I usually detail the history of how terms have been utilized, but I fear it will leave you even more confused. Suffice it to say that the original lesion described as a NT is a nerve sheath myxoma and the cellular NT (CNT) is a distinct lesion of probable fibrohistiocytic origin. (1)
The following is the abstract of the seminal work of Barnhill and Mihm in 1990 clarifying the nature of CNT that is still apt today: “We describe the clinical, histopathologic, and immunohistochemical characteristics of five examples of a distinctive subtype of neurothekeoma we term ‘cellular neurothekeoma’ (CNT). These lesions are nondescript papules or nodules primarily involving the head and neck areas of young adults. Histopathologically, CNT are fairly well-defined proliferations involving the reticular dermis; they consist of fascicles of polygonal and spindle cells with eosinophilic or pale-staining cytoplasm and neuroid characteristics. Low-grade cytologic atypia and mitotic activity are common. All immunohistochemical markers — including S-100 protein, myelin basic protein, epithelial membrane antigen, and histiocytic antigens — have failed to show positivity in our laboratory. Separation from myxomatous variants of neurothekeoma is based on greater cellularity, less myxomatous change, and less pronounced plexiform compartmentalization by fibrous septae, which resemble perineurium. The histopathologic differential diagnosis usually includes spindle and epithelioid cell (Spitz) nevus, malignant melanoma (particularly desmoplastic-neurotropic melanoma), cellular blue nevus, and fibrohistiocytic proliferations. The recognition of CNT and its differentiation from melanoma are important so that overly aggressive therapy is avoided.” (2)
CNTs are most commonly seen in children and young adults, with a female predominance. Lesions usually present as solitary, painless, slow-growing, pink-tan to reddish-brown papules or nodules, predominantly on the head and neck or upper trunk. (3) Only rarely are multiple CNTs appreciated. Lau et al reported such a case of “multiple myxoid” CNTs in a 60-year-old woman with systemic lupus erythematosus. (4) Zhao and Koh reported the case of CNT in a 10-year-old boy within the field of prior radiation therapy for a medulloblastoma — it is unclear if this was coincidental or if the radiation was etiologic. (5) In their experience with 7 cases of pediatric CNT and a systematic review of 71 cases from the literature, Murphrey et al note that in children, lesions are most commonly found on the body, favoring the upper limbs, rather than the head or neck, compared to adult CNTs, which are most commonly found on the upper limbs, head, and neck. The clinical differential diagnosis for CNTs includes juvenile xanthogranuloma, Spitz nevus, amelanotic melanoma, basal cell carcinoma, dermatofibroma, keloid, insect bite, cutaneous lymphoid hyperplasia, and lymphomatoid papulosis. (6,7) Dermoscopic features include arborizing vessels and white streaks corresponding to peripheral fibrosis and fibrous septae. (8)
The histologic diagnosis of CNT is an exercise in clinicopathological correlation because there are no specific immunohistochemical stains to confirm the diagnosis. CNTs almost always stain positively with NKI-C3 (clone CD63) and CD10 and negatively for epithelial membrane antigen. S-100 protein and Melan-A are not expressed, differentiating them from melanocytic lesions. (3) PRAME (preferentially expressed antigen in melanoma) was shown to be variably expressed in 11 cases of NT, confirming the fact that this marker is not restricted to malignant tumors. (9)
CNTs are considered benign lesions. Regardless, atypical histologic features may pose diagnostic challenges. As stated by Pedroni et al: “Possible atypical findings include infiltrative growth, cytologic atypia, marked proliferative activity, vascular or perineural invasion, myxoid stroma, fascicular and plexiform growth patterns. In markedly atypical cases, immunostaining is not sufficient for differentiating CNT from atypical fibroxanthoma or undifferentiated pleomorphic sarcoma, since those entities can be positive for NKI/C3 and CD10, giving reason of the great difficulties encountered by pathologists in the diagnostic process.” (10) Except for a case of a 7-year-old male with CNT of the nasal vestibule with cervical metastasis (11), even with histologic features of aggressive behavior, there are no other cases of metastatic disease. Because of the remote possibility of clinically aggressive behavior, complete surgical excision of CNT with negative margins is advised. (12) Regardless of atypical features, recurrence rates are low following complete surgical excision. In cosmetically sensitive areas, Mohs micrographic surgery may be valuable. (1)
In conclusion, CNTs are benign lesions of presumed fibrohistiocytic lineage, that may appear disconcerting histologically. The world could use more people like Ray Barnhill and Marty Mihm to help us sort out the nature of these enigmatic lesions. We are most fortunate to have Dr. Raymond Barnhill, the 2023 recipient of the American Society of Dermatopathology’s Walter R. Nickel Award for Excellence in Teaching Dermatopathology, and the lead author of the 1990 paper on CNT, to provide our expert’s viewpoint.
Point to Remember: Cellular neurothekeomas are benign lesions of presumed fibrohistiocytic origin. Rendering this diagnosis is essential to avoid misdiagnosis and potential overtreatment.
Our expert’s viewpoint
Raymond Barnhill, MD, FAAD
The first case of cellular neurothekeoma (CNTK) that I encountered was a tumor that came across my desk with a diagnosis of desmoplastic melanoma. Although a dermal spindle cell tumor with fibrous stroma and some myxoid alteration, I thought that the subtle, more organized fascicular architecture, cellularity, and cytomorphology were not typical of desmoplastic melanoma. Recalling Gallagher and Helwig’s 1980 publication on “neurothekeoma,” it struck me that this could be a more “cellular” subtype of this entity. With the subsequent collection of four additional cases with comparable findings and absence of expression of S100 protein, the new entity was then reported as “cellular neurothekeoma.” Over the years, I have been struck by the degree to which this entity may be confused with melanocytic lesions, especially melanoma or spitzoid tumors. Distinction of CNTK from melanoma is highly important to avoid overdiagnosis of melanoma and potentially overly aggressive therapies. With greater characterization of CNTK, neural differentiation appears less well substantiated or not present. However, without more sophisticated study, it may not yet be possible to exclude some link to neural or neural crest differentiation with complete certainty.
Kao EY, Kernig ML. Neurothekeoma. 2021 Nov 14. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30137810.
Barnhill RL, Mihm MC Jr. Cellular neurothekeoma. A distinctive variant of neurothekeoma mimicking nevomelanocytic tumors. Am J Surg Pathol. 1990 Feb;14(2):113-20. doi: 10.1097/00000478-199002000-00002. PMID: 2154139.
Stewart T, Cachia A, Frew J. Cellular neurothekeoma. Int J Womens Dermatol. 2021 Jul 31;7(5Part B):835-837. doi: 10.1016/j.ijwd.2021.07.011. PMID: 35028394; PMCID: PMC8714564.
Lau SK, Cassarino DS, Koh SS. Multiple myxoid cellular neurothekeomas in a patient with systemic lupus erythematosus. J Cutan Pathol. 2021 Jul;48(7):980-985. doi: 10.1111/cup.14025. Epub 2021 May 9. PMID: 33844324.
Zhao Z, Koh MJA. Cellular neurothekeoma occurring at the site of radiation therapy in a child with medulloblastoma. Pediatr Dermatol. 2022 May;39(3):488-490. doi: 10.1111/pde.14941. Epub 2022 Feb 17. PMID: 35178793.
Murphrey M, Huy Nguyen A, White KP, Krol A, Bernert R, Yarbrough K. Pediatric cellular neurothekeoma: Seven cases and systematic review of the literature. Pediatr Dermatol. 2020 Mar;37(2):320-325. doi: 10.1111/pde.14043. Epub 2020 Jan 12. PMID: 31930561.
Płaszczyńska A, Sławińska M, Sobjanek M. The role of dermoscopy in the diagnosis of neurothekeoma - personal observations and review of previously reported cases. Int J Dermatol. 2022 Sep;61(9):1145-1147. doi: 10.1111/ijd.16130. Epub 2022 Mar 14. PMID: 35285516.
Bortoluzzi P, Romagnuolo M, Mandolini PL, Berti E, Boggio F. Dermatoscopy of cellular neurothekeoma. JAAD Case Rep. 2022 Feb 8;22:14-17. doi: 10.1016/j.jdcr.2022.01.036. PMID: 35265740; PMCID: PMC8899132.
Cesinaro AM, Piana S, Paganelli A, Pedroni G, Santandrea G, Maiorana A. PRAME expression in cellular neurothekeoma: A study of 11 cases. J Cutan Pathol. 2022 Apr;49(4):338-342. doi: 10.1111/cup.14163. Epub 2021 Nov 22. PMID: 34761425.
Pedroni G, Paganelli A, Bassoli S, Kutzner H, Cesinaro AM, Magnoni C. Atypical cellular neurothekeoma: Report of a case. Dermatol Reports. 2021 Dec 28;14(2):9327. doi: 10.4081/dr.2022.9327. PMID: 35795835; PMCID: PMC9251521.
Zenner K, Dahl J, Deutsch G, Rudzinski E, Bly R, Perkins JA. Metastatic cellular neurothekeoma in childhood. Int J Pediatr Otorhinolaryngol. 2019 Apr;119:86-88. doi: 10.1016/j.ijporl.2019.01.027. Epub 2019 Jan 22. PMID: 30685663; PMCID: PMC7017924.
D'Alessandris N, Picchetto A, Pignataro MG, Cerbelli B, Manzo D, Rocca CD, d'Amati G, Pernazza A. Atypical cellular neurothekeoma (ACN) of the elderly: case report and brief review of the literature. Pathologica. 2020 Dec;112(4):210-213. doi: 10.32074/1591-951X-104. PMID: 33393524; PMCID: PMC8183354.
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