Skip to main content

Advertisement

SpringerLink
Log in

Pathologic remodeling in human neuromas: insights from clinical specimens

  • Original Article - Peripheral Nerves
  • Published:
Acta Neurochirurgica Aims and scope Submit manuscript

Abstract

Background

Neuroma pathology is commonly described as lacking a clear internal structure, but we observed evidence that there are consistent architectural elements. Using human neuroma samples, we sought to identify molecular features that characterize neuroma pathophysiology.

Methods

Thirty specimens—12 neuromas-in-continuity (NICs), 11 stump neuromas, two brachial plexus avulsions, and five controls—were immunohistochemically analyzed with antibodies against various components of normal nerve substructures.

Results

There were no substantial histopathologic differences between stump neuromas and NICs, except that NICs had intact fascicle(s) in the specimen. These intact fascicles showed evidence of injury and fibrosis. On immunohistochemical analysis of the neuromas, laminin demonstrated a consistent double-lumen configuration. The outer lumen stained with GLUT1 antibodies, consistent with perineurium and microfascicle formation. Antibodies to NF200 revealed small clusters of small-diameter axons within the inner lumen, and the anti-S100 antibody showed a relatively regular pattern of non-myelinating Schwann cells. CD68+ cells were only seen in a limited temporal window after injury. T-cells were seen in neuroma specimens, with both a temporal evolution as well as persistence long after injury. Avulsion injury specimens had similar architecture to control nerves. Seven pediatric specimens were not qualitatively different from adult specimens. NICs demonstrated intact but abnormal fascicles that may account for the neurologically impoverished outcomes from untreated NICs.

Conclusions

We propose that there is consistent pathophysiologic remodeling after fascicle disruption. Particular features, such as predominance of small caliber axons and persistence of numerous T-cells long after injury, suggest a potential role in chronic pain associated with neuromas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Brown-Séquard C (1881) On certain physiological effects of stretching of the sciatic nerve. Lancet 117:206

    Article  Google Scholar 

  2. Bunge M, Wood P, Tynan L, Bates M, Sanes (1989) Perineurium originates from fibroblasts: demonstration in vitro with a retroviral marker. Science 243:229–231. https://doi.org/10.1126/science.2492115

    Article  CAS  PubMed  Google Scholar 

  3. Burks SS, Cajigas I, Jose J, Levi AD (2017) Intraoperative imaging in traumatic peripheral nerve lesions: correlating histologic cross-sections with high-resolution ultrasound. Oper Neurosurg (Hagerstown) 13:196–203. https://doi.org/10.1093/ons/opw016

    Article  Google Scholar 

  4. Carlton SM, Dougherty PM, Pover CM, Coggeshall RE (1991) Neuroma formation and numbers of axons in a rat model of experimental peripheral neuropathy. Neurosci Lett 131:88–92. https://doi.org/10.1016/0304-3940(91)90343-R

    Article  CAS  PubMed  Google Scholar 

  5. Cattin AL, Burden JJ, Van Emmenis L, Mackenzie FE, Hoving JJ, Garcia Calavia N, Guo Y, McLaughlin M, Rosenberg LH, Quereda V, Jamecna D, Napoli I, Parrinello S, Enver T, Ruhrberg C, Lloyd AC (2015) Macrophage-induced blood vessels guide Schwann cell-mediated regeneration of peripheral nerves. Cell 162:1127–1139. https://doi.org/10.1016/j.cell.2015.07.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen S, Rio C, Ji R-R, Dikkes P, Coggeshall RE, Woolf CJ, Corfas G (2003) Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss. Nat Neurosci 6:1186. https://doi.org/10.1038/nn1139

    Article  CAS  PubMed  Google Scholar 

  7. Chen ZL, Yu WM, Strickland S (2007) Peripheral regeneration. Annu Rev Neurosci 30:209–233. https://doi.org/10.1146/annurev.neuro.30.051606.094337

    Article  CAS  PubMed  Google Scholar 

  8. Chiono V, Tonda-Turo C, Ciardelli G (2009) Chapter 9: artificial scaffolds for peripheral nerve reconstruction. Int Rev Neurobiol 87:173–198. https://doi.org/10.1016/S0074-7742(09)87009-8

    Article  CAS  PubMed  Google Scholar 

  9. Dailey AT, Avellino AM, Benthem L, Silver J, Kliot M (1998) Complement depletion reduces macrophage infiltration and activation during Wallerian degeneration and axonal regeneration. J Neurosci 18:6713–6722

    Article  CAS  Google Scholar 

  10. Denny-Brown D (1946) Importance of neural fibroblasts in the regeneration of nerve. Arch Neurol Psychiatr 55:171–215

    Article  CAS  Google Scholar 

  11. Fregnan F, Muratori L, Simoes AR, Giacobini-Robecchi MG, Raimondo S (2012) Role of inflammatory cytokines in peripheral nerve injury. Neural Regen Res 7:2259–2266. https://doi.org/10.3969/j.issn.1673-5374.2012.29.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Frisen J, Risling M, Fried K (1993) Distribution and axonal relations of macrophages in a neuroma. Neuroscience 55:1003–1013

    Article  CAS  Google Scholar 

  13. Gottfried E, Kunz-Schughart LA, Weber A, Rehli M, Peuker A, Muller A, Kastenberger M, Brockhoff G, Andreesen R, Kreutz M (2008) Expression of CD68 in non-myeloid cell types. Scand J Immunol 67:453–463. https://doi.org/10.1111/j.1365-3083.2008.02091.x

    Article  CAS  PubMed  Google Scholar 

  14. Haftek J (1970) Stretch injury of peripheral nerve. Acute effects of stretching on rabbit nerve. J Bone Joint Surg (Br) 52:354–365

    Article  CAS  Google Scholar 

  15. Hartlehnert M, Derksen A, Hagenacker T, Kindermann D, Schafers M, Pawlak M, Kieseier BC, Meyer Zu Horste G (2017) Schwann cells promote post-traumatic nerve inflammation and neuropathic pain through MHC class II. Sci Rep 7:12518. https://doi.org/10.1038/s41598-017-12744-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hirose T, Tani T, Shimada T, Ishizawa K, Shimada S, Sano T (2003) Immunohistochemical demonstration of EMA/Glut1-positive perineurial cells and CD34-positive fibroblastic cells in peripheral nerve sheath tumors. Mod Pathol 16:293–298. https://doi.org/10.1097/01.MP.0000062654.83617.B7

    Article  PubMed  Google Scholar 

  17. Holmes W, Young JZ (1942) Nerve regeneration after immediate and delayed suture. J Anat 77(63–96):10

    PubMed  Google Scholar 

  18. Holness CL, Simmons DL (1993) Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood 81:1607–1613

    Article  CAS  Google Scholar 

  19. Jung J, Hahn P, Choi B, Mozaffar T, Gupta R (2014) Early surgical decompression restores neurovascular blood flow and ischemic parameters in an in vivo animal model of nerve compression injury. J Bone Joint Surg Am 96:897–906. https://doi.org/10.2106/JBJS.M.01116

    Article  PubMed  PubMed Central  Google Scholar 

  20. Jurecka W, Ammerer HP, Lassmann H (1975) Regeneration of a transected peripheral nerve. An autoradiographic and electron microscopic study. Acta Neuropathol 32:299–312

    Article  CAS  Google Scholar 

  21. Kaiserling E, Xiao JC, Ruck P, Horny HP (1993) Aberrant expression of macrophage-associated antigens (CD68 and Ki-M1P) by Schwann cells in reactive and neoplastic neural tissue. Light- and electron-microscopic findings. Mod Pathol 6:463–468

    CAS  PubMed  Google Scholar 

  22. Karsy M, Palmer CA, Mahan MA (2018) Pathologic remodeling of endoneurial tubules in human neuromas. Cureus 10:e2087. https://doi.org/10.7759/cureus.2087

    Article  PubMed  PubMed Central  Google Scholar 

  23. Katenkamp D, Stiller D (1978) Ultrastructure of perineurial cells during peripheral nerve regeneration. Electron microscopical investigations on the so-called amputation neuroma. Exp Pathol (Jena) 16:5–15

    CAS  Google Scholar 

  24. Kingham PJ, Kalbermatten DF, Mahay D, Armstrong SJ, Wiberg M, Terenghi G (2007) Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro. Exp Neurol 207:267–274

    Article  CAS  Google Scholar 

  25. Kleinschnitz C, Hofstetter HH, Meuth SG, Braeuninger S, Sommer C, Stoll G (2006) T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression. Exp Neurol 200:480–485. https://doi.org/10.1016/j.expneurol.2006.03.014

    Article  CAS  PubMed  Google Scholar 

  26. Kucenas S, Takada N, Park H-C, Woodruff E, Broadie K, Appel B (2008) CNS-derived glia ensheath peripheral nerves and mediate motor root development. Nat Neurosci 11:143. https://doi.org/10.1038/nn2025 https://www.nature.com/articles/nn2025#supplementary-information

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kunz-Schughart LA, Weber A, Rehli M, Gottfried E, Brockhoff G, Krause SW, Andreesen R, Kreutz M (2003) The “classical” macrophage marker CD68 is strongly expressed in primary human fibroblasts. Verh Dtsch Ges Pathol 87:215–223

    CAS  PubMed  Google Scholar 

  28. Lees JG, Duffy SS, Perera CJ, Moalem-Taylor G (2015) Depletion of Foxp3+ regulatory T cells increases severity of mechanical allodynia and significantly alters systemic cytokine levels following peripheral nerve injury. Cytokine 71:207–214. https://doi.org/10.1016/j.cyto.2014.10.028

    Article  CAS  PubMed  Google Scholar 

  29. Lewis GM, Kucenas S (2014) Perineurial glia are essential for motor axon regrowth following nerve injury. J Neurosci 34:12762–12777. https://doi.org/10.1523/JNEUROSCI.1906-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mahan MA (2018) Nerve stretching: a history of tension. J Neurosurg. https://doi.org/10.3171/2018.8.JNS173181

  31. Malik RA, Tesfaye S, Newrick PG, Walker D, Rajbhandari SM, Siddique I, Sharma AK, Boulton AJM, King RHM, Thomas PK, Ward JD (2005) Sural nerve pathology in diabetic patients with minimal but progressive neuropathy. Diabetologia 48:578–585. https://doi.org/10.1007/s00125-004-1663-5

    Article  CAS  PubMed  Google Scholar 

  32. Masson P (1932) Experimental and spontaneous schwannomas (peripheral gliomas): I. Experimental schwannomas. Am J Pathol 8(367–388):361

    Google Scholar 

  33. Mohseni S, Badii M, Kylhammar A, Thomsen NOB, Eriksson KF, Malik RA, Rosen I, Dahlin LB (2017) Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: implications for diabetic neuropathy. Brain Behav 7:e00763. https://doi.org/10.1002/brb3.763

    Article  PubMed  PubMed Central  Google Scholar 

  34. Muona P, Sollberg S, Peltonen J, Uitto J (1992) Glucose transporters of rat peripheral nerve. Differential expression of GLUT1 gene by Schwann cells and perineural cells in vivo and in vitro. Diabetes 41:1587–1596

    Article  CAS  Google Scholar 

  35. Myers RR, Heckman HM, Galbraith JA, Powell HC (1991) Subperineurial demyelination associated with reduced nerve blood flow and oxygen tension after epineurial vascular stripping. Lab Investig 65:41–50

    CAS  PubMed  Google Scholar 

  36. Nageotte J (1932) Sheaths of the peripheral nerves. Nerve degeneration and regeneration. In: Penfield W (ed) Cytology and cellular pathology of the nervous system. Hoeber, New York

    Google Scholar 

  37. Odier L (1811) Manuel de Medecine Pratique, 2nd ed. J. Paschoud, Paris

    Google Scholar 

  38. Parrinello S, Napoli I, Ribeiro S, Digby PW, Fedorova M, Parkinson DB, Doddrell RD, Nakayama M, Adams RH, Lloyd AC (2010) EphB signaling directs peripheral nerve regeneration through Sox2-dependent Schwann cell sorting. Cell 143:145–155

    Article  CAS  Google Scholar 

  39. Perry V, Brown M, Gordon S (1987) The macrophage response to central and peripheral nerve injury. A possible role for macrophages in regeneration. J Exp Med 165:1218–1223

    Article  CAS  Google Scholar 

  40. Pina AR, Martinez MM, de Almeida OP (2015) Glut-1, best immunohistochemical marker for perineurial cells. Head Neck Pathol 9:104–106. https://doi.org/10.1007/s12105-014-0544-6

    Article  PubMed  Google Scholar 

  41. Ramon y Cajal S, DeFelipe J, Jones E (eds) (1991) Cajal's degeneration and regeneration of the nervous system. Oxford University Press, Oxford

    Google Scholar 

  42. Richard L, Topilko P, Magy L, Decouvelaere A-V, Charnay P, Funalot B, Vallat J-M (2012) Endoneurial fibroblast-like cells. J Neuropathol Exp Neurol 71:938–947

    Article  CAS  Google Scholar 

  43. Schlaepfer WW (1987) Presidential address: neurofilaments: structure, metabolism and implications in disease. J Neuropathol Exp Neurol 46:117–129. https://doi.org/10.1097/00005072-198703000-00001

    Article  CAS  PubMed  Google Scholar 

  44. Schroder JM, May R, Weis J (1993) Perineurial cells are the first to traverse gaps of peripheral nerves in silicone tubes. Clin Neurol Neurosurg 95(Suppl):S78–S83

    Article  Google Scholar 

  45. Sunderland S (1951) A classification of peripheral nerve injuries producing loss of function. Brain 74:491–516

    Article  CAS  Google Scholar 

  46. Tannemaat MR, Korecka J, Ehlert EME, Mason MRJ, van Duinen SG, Boer GJ, Malessy MJA, Verhaagen J (2007) Human neuroma contains increased levels of semaphorin 3A, which surrounds nerve fibers and reduces neurite extension in vitro. J Neurosci 27:14260–14264. https://doi.org/10.1523/jneurosci.4571-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Thomas PK, Jones DG (1967) The cellular response to nerve injury. II Regeneration of the perineurium after nerve section. J Anat 101:45–55

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Tserentsoodol N, Shin BC, Koyama H, Suzuki T, Takata K (1999) Immunolocalization of tight junction proteins, occludin and ZO-1, and glucose transporter GLUT1 in the cells of the blood-nerve barrier. Arch Histol Cytol 62:459–469

    Article  CAS  Google Scholar 

  49. van Vliet AC, Tannemaat MR, van Duinen SG, Verhaagen J, Malessy MJ, De Winter F (2015) Human neuroma-in-continuity contains focal deficits in myelination. J Neuropathol Exp Neurol 74:901–911. https://doi.org/10.1097/nen.0000000000000229

    Article  PubMed  Google Scholar 

  50. Weis J, May R, Schroder JM (1994) Fine structural and immunohistochemical identification of perineurial cells connecting proximal and distal stumps of transected peripheral nerves at early stages of regeneration in silicone tubes. Acta Neuropathol 88:159–165

    Article  CAS  Google Scholar 

  51. Wood W (1829) Observations on neuromas. With cases and histories of the disease. Trans Med Chir Soc Edinb 3:367–434

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 North Medical Drive East, Salt Lake City, UT, 84132, USA

    Mark A. Mahan, Michael Karsy, Wesley Warner & Stewart Yeoh

  2. Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Hussam Abou-Al-Shaar

  3. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    Cheryl A. Palmer

Authors
  1. Mark A. Mahan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hussam Abou-Al-Shaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Karsy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wesley Warner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stewart Yeoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cheryl A. Palmer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark A. Mahan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants or animals

All human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

The study was approved by the institutional review board at the University of Utah with wavier of informed consent from the patients involved in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Comments

An ambitious and interesting article that examines the histopathology of various types of human neuromas (stump, in continuity, and avulsion types) as compared to normal control nerve specimens using standard as well as immunohistochemical tissue staining techniques. Despite some attempt at quantification (e.g., axon diameters shown in Fig. 3c), most of the observations made are qualitative in nature. Many of the observations are reasonable and supported by other studies both in humans and animals. The authors do comment on the surprising finding of little staining of macrophages using CD68 in most of their tissue specimens and provide some possible explanations. In future studies, it would be interesting to stain their tissue specimens for proteoglycans which have been shown to play a role in influencing axonal regeneration following nerve injury.

Michel Kliot

CA, USA

This article is part of the Topical Collection on Peripheral Nerves

Electronic supplementary material

ESM 1

(DOCX 7816 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mahan, M.A., Abou-Al-Shaar, H., Karsy, M. et al. Pathologic remodeling in human neuromas: insights from clinical specimens. Acta Neurochir 161, 2453–2466 (2019). https://doi.org/10.1007/s00701-019-04052-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00701-019-04052-7

Keywords

Search

Navigation