Exuberant circumferential fibroproliferative neuromas in lipomatosis of nerve: a unifying theory. Illustrative case

Andres A Maldonado Departments of Neurologic Surgery,

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Mark A Mahan Department of Neurological Surgery, University of Utah, Salt Lake City, Utah; and

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Jodi M Carter Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada

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Kimberly K Amrami Radiology, Mayo Clinic, Rochester, Minnesota;

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Tomas Marek Departments of Neurologic Surgery,

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Robert J Spinner Departments of Neurologic Surgery,

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BACKGROUND

Lipomatosis of nerve (LN) is a rare disorder characterized by the massive enlargement of peripheral nerves, frequently accompanied by generalized fibroadipose proliferation and skeletal overgrowth.

OBSERVATIONS

The authors have been routinely following a 20-year-old male for lipomatosis of median nerve at the wrist noted shortly after birth. He had undergone resection of the lesion accompanied by sural nerve grafting at another institution. Clinically, although his neurological loss of function has been stable, he has had continued soft tissue growth. Serial magnetic resonance imaging has revealed persistent LN proximal to the repair sites with evidence of fatty proliferation in the sural grafts and continued LN and fatty proliferation distally. There has been a progressive circumferential pattern of fibrosis around the proximal and distal suture lines, which has a similar radiological pattern to desmoid type fibromatosis (a pattern recently described in neuromuscular choristoma [NMC] desmoid-type fibromatosis).

LESSONS

Considering the similar reaction of nerve in both LN and NMC despite differing genetic cascades, the authors believe a unifying process occurs in both lesions. The pattern of circumferential fibroproliferation would be most consistent with neuron-mediated growth from unspecified trophic factors, supporting a previously reported a nerve-derived “inside-out mechanism.” The clinical consequences of this unifying process are presented.

ABBREVIATIONS

DTF = desmoid-type fibromatosis; LN = lipomatosis of nerve; MRI = magnetic resonance imaging; NMC = neuromuscular choristoma; US = ultrasound

BACKGROUND

Lipomatosis of nerve (LN) is a rare disorder characterized by the massive enlargement of peripheral nerves, frequently accompanied by generalized fibroadipose proliferation and skeletal overgrowth.

OBSERVATIONS

The authors have been routinely following a 20-year-old male for lipomatosis of median nerve at the wrist noted shortly after birth. He had undergone resection of the lesion accompanied by sural nerve grafting at another institution. Clinically, although his neurological loss of function has been stable, he has had continued soft tissue growth. Serial magnetic resonance imaging has revealed persistent LN proximal to the repair sites with evidence of fatty proliferation in the sural grafts and continued LN and fatty proliferation distally. There has been a progressive circumferential pattern of fibrosis around the proximal and distal suture lines, which has a similar radiological pattern to desmoid type fibromatosis (a pattern recently described in neuromuscular choristoma [NMC] desmoid-type fibromatosis).

LESSONS

Considering the similar reaction of nerve in both LN and NMC despite differing genetic cascades, the authors believe a unifying process occurs in both lesions. The pattern of circumferential fibroproliferation would be most consistent with neuron-mediated growth from unspecified trophic factors, supporting a previously reported a nerve-derived “inside-out mechanism.” The clinical consequences of this unifying process are presented.

ABBREVIATIONS

DTF = desmoid-type fibromatosis; LN = lipomatosis of nerve; MRI = magnetic resonance imaging; NMC = neuromuscular choristoma; US = ultrasound

Lipomatosis of nerve (LN), also called “fibrolipomatous” or “lipofibromatous hamartoma,”1 is a congenital lesion characterized by the presence of fat interspersed within nerve.2 Patients typically present before 30 years of age, often at birth or in early childhood, with nerve symptoms and findings often related to a mass. The most common site is the median nerve within the carpal tunnel region, though it has been reported at many sites3 but, interestingly, not in the central nervous system. In nearly 70% of cases, it is associated with bony and soft tissue overgrowth in the nerve territory.4 In extreme cases of overgrowth, this condition has been referred to as “macrodystrophia lipomatosa.” LN is part of the PIK3CA-related overgrowth spectrum.5

Our group has previously reported the imaging features of soft tissue proliferation in neuromas in LN after iatrogenic injury.6 We observed a direct correlation between the extent of the injury and the degree of tissue proliferation, ranging from no proliferative change with decompression alone to minor changes with partial injury after fascicular biopsy to more extensive changes in cases of subtotal debulking or neurectomy/nerve resection. We previously reported on an 8-year clinical and radiological follow-up of an infant treated with nerve resection and grafting of lipomatosis of median nerve in the palm and wrist7 to define progressive overgrowth after subtotal resection.8 This patient was reported to emphasize that attempted resection of the LN still resulted in continued evidence of nerve territory overgrowth clinically and radiologically.8 Given the rarity of patients treated with the combination of nerve resection and grafting and the lack of any other reports with a documented long-term follow-up, we advocated caution for any aggressive surgical approach to LN; in similar cases we have favored neurolysis, tunnel release for nerve-related compression of mixed nerves, and soft tissue/bony procedures for function, cosmesis, and deformity.

Herein, we provide another decade of follow-up in this case and introduce a unifying theory to explain the exuberant circumferential proliferation at the proximal and distal suture lines and to demonstrate the extent of progressive nerve territory soft tissue overgrowth (Fig. 1). We believe these two findings shed important mechanistic information on the trophic nature underlying the overgrowth.

FIG. 1
FIG. 1

A–C: Interval clinical growth of the radial side of the palm, particularly the first web space and the hypertrophic scar over the past 15 years.

Illustrative Case

A 20-year-old male was seen in follow-up for his known and previously grafted median nerve at the wrist for attempted treatment of LN. At age 2, the boy had presented with a palmar mass not associated with other skeletal or dermatological abnormalities. The initial clinical evaluation of the mass was performed and included an ultrasound (US) and magnetic resonance imaging (MRI); both were consistent with LN. One year later at age 3, he was treated at another institution with nerve resection and sural nerve cable grafting from the distal forearm to the palm.7 Nerve pathology was consistent with an LN. At the 8-year follow-up,8 there was evidence of a recurrence or persistence of the LN. We found clinical soft tissue (but not bony) overgrowth as well as a hypertrophic scar. Serial MRI showed an LN proximal to the proximal nerve repair; fibroadipose enlargement of the interpositional nerve grafts, and extension of the lipomatous process into the distal nerve coaptation and thenar muscle atrophy. The abnormal proliferative response at the suture line was also evident.

The patient has been followed both clinically and with serial MRI every few years at our institution. Clinically, although his neurological loss of function has been stable (mild median nerve symptoms with 2-point discrimination of 8 mm in all fingers, useful thumb opposition despite weakness of the abductor pollicis brevis, and Tinel’s sign just above the wrist), he has experienced further lipomatous soft tissue overgrowth in the palm and first web space (Fig. 1). MRI demonstrated exuberant proliferation at the proximal and distal suture lines that had a radiological appearance similar to that of desmoid-type fibromatosis (DTF) with a mild change in the shape of the enhancing nodular soft tissue along the median nerve (Fig. 2). High-resolution 7-T MRI recently demonstrated a circumferential pattern of enhancing nodular soft tissue along the median nerve in the distal forearm measuring 1.8 × 1.8 × 2.5 cm (Figs. 3 and 4). Mild overgrowth was seen in the most radial nodule (measuring 1.4 × 0.9 × 1.5 cm, previously 1.2 × 1.1 × 1.4 cm). There was continued radiological progression of the LN proximal to the proximal suture line, within the grafts and especially distal to the distal suture line (Fig. 5), although it was present on the first postoperative MRI studies in 2008. He underwent US-guided needle biopsy at three different sites of contrast-enhancing lesions: 1) distal forearm mass; 2) palmar soft tissue nodules about the second and third digits; and 3) lipomatous hypertrophic process involving the second digit. All were consistent with LN, but supportive molecular genetic studies for PIK3CA mutations could not be performed due to insufficient tissue in the biopsies.

FIG. 2
FIG. 2

Artistic rendering showing that the sequelae of nerve resection and grafting of LN may include continued bony and soft tissue overgrowth and fibrous proliferation (with permission, Mayo Foundation, 2023) (A and B). Postcontrast coronal T1 spoiled gradient recalled echo (SPGR) MRI (C and D) shows the nodular enhancing mass-like lesions in the distal forearm and at the palm corresponding with the proximal suture line in the median nerve and the distal sutures in the digital nerves. Abnormal fatty proliferation can be seen around the nerve grafts between the nodular masses at the proximal and distal suture lines.

FIG. 3
FIG. 3

Axial T1-weighted MRI (A–H) shows the circumferential encasement of fascicles in the proximal suture line in the distal forearm sequentially from proximal to distal. In the middle, there is loss of complete architecture. Just above and below, however, there is fibrosis around the fascicular bundles. Note that LN is visible proximal to the proximal suture line.

FIG. 4
FIG. 4

Corresponding axial postcontrast T1 SGPR (spoiled gradient recalled echo) MRI (A–H) shows the enhancement.

FIG. 5
FIG. 5

Axial T1-weighted MR images (AC) show the progressive fatty overgrowth occurring in the distal palm. These provide 18-year postoperative follow-up studies since subtotal resection of the LN and nerve grafting. Asterisk indicates the radial digital nerve to the index finger; plus sign, the second common digital nerve; white arrow, third common digital nerve.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

The progressive circumferential encasement of the median nerve in this patient is consistent with and extends previous observations in patients with LN and proliferative neuromas at the short-term follow-up.6 Advances with a similar developmental condition of neuromuscular choristoma (NMC) call into play a possible shared mechanism of nerve tissue overgrowth in response to intrinsic or iatrogenic stimulation. NMC, a developmental lesion of peripheral nerve characterized by the intercalation of skeletal muscle fibers within nerve, has also been associated with nerve territory sequelae, including neuropathy, distal territory undergrowth, but also perilesional soft tissue proliferation in the form of NMC-associated DTF (NMC-DTF).9,10 NMCs are most common in proximal nerves such as the sciatic/lumbosacral plexus and brachial plexus. Both NMC and NMC-DTF have been associated with activating mutations in CTNNB1, which encodes beta-catenin. Biopsy and surgery on the NMC11 and even trauma to the region may trigger the development of NMC-DTF.12,13 Recently, we reported evidence of nerve territory circumferential encasement of NMC by NMC-DTF, arguing that this observation supports a nerve-associated mechanism of NMC-DTF development.12 Considering the observation of perilesional soft tissue overgrowth in both LN and NMC, despite their association with different pathogenic genetic mutations (in PIK3CA and CTNNB1, respectively), we hypothesize that the axons from nerve injury (or during regeneration) promote excessive growth in the adjacent soft tissues (“inside-out mechanism”), which also harbor the genetic mutation. Although the regional tissue may be primed for overgrowth, it needs a trigger, which seems to arise from a neural signal.

Observations

The similar MRI findings of LN and NMC support this proposed unifying mechanism of soft tissue proliferation in LN and NMC. These studies show the progressive development of abnormal, avidly enhancing, and nodular soft tissue at the proximal and distal aspects of the nerve coaptation, encasing the nerve. The exuberant fibroproliferation of LN at the iatrogenic site of injury, including the suture lines on MRI in this case, may mimic NMC-DTF. To date, however, there have been no cases of NMC-DTF in patients with LN4,5; a previous case reported as an LN by Lee et al.,14 had radiological features consistent with NMC rather than LN.15

In the current case, LN was confirmed in all three locations by percutaneous biopsy, with no features suggestive of NMC or NMC-DTF. Our previous study of neuroma formation was consistent with neuroma, fibrosis, LN, or foreign giant-cell reaction without any features of DTF.7 Although it is common to develop neuromas at the site of nerve grafting, they would typically involve enlargement of the nerve with the loss of normal fascicular architecture with limited enhancement that usually reflects fibrosis; in our case, the florid and circumferential nodular soft tissue growth at the proximal and distal suture lines is more akin to the appearance of DTF, with the nerve effectively encased at these points and with the loss of the distinct, individual nerve bundles at the suture lines. However, the individual low signal and individual nerve bundles between the nerve repairs can be seen running through the nodular enhancing soft tissue, encasing the nerves and extending from the sites of the repairs (well demonstrated on the coronal postcontrast images). Separately, fatty infiltration of the nerve between the ends of the grafted nerve and enhancing soft tissue persists and has even become more prominent over time.

Lessons

Although we hypothesize that the perilesional circumferential growth pattern of soft tissue proliferative lesions in LN and NMC is attributable to neuron-derived signals leading to proliferation in susceptible soft tissue microenvironments, there are many unanswered questions. Because of lesional tissue exhaustion, we were unable to perform molecular genetic testing on any of the diagnostic biopsies. In the current case, we cannot exclude the possibility that the interposed sural nerve grafts harbor a PIK3CA mutation as well. This patient will be followed long term with comprehensive molecular genetic testing of any subsequent tissue samples to test our hypotheses. In any event, the clinical impact of this case is clear, supporting our prior cautions regarding attempted nerve grafting of an LN as a method to prevent or control disease progression.

Considering the similar reaction of nerve in both LN and NMC despite differing genetic cascades, we believe a unifying process occurs in both lesions. Based on our imaging observation, the pattern of circumferential fibroproliferation would be most consistent with neuron-mediated growth from unspecified trophic factors, supporting a previously reported a nerve-derived inside-out mechanism, rather than from the field effect from neighboring tissues in the nerve territory. Clinical consequences of this unifying process are presented.

Author Contributions

Conception and design: Spinner, Carter, Amrami. Acquisition of data: Spinner, Maldonado, Amrami, Marek. Analysis and interpretation of data: Spinner, Maldonado, Carter, Amrami, Marek. Drafting the article: Spinner, Maldonado, Carter, Amrami. Critically revising the article: all authors. Reviewed submitted version of manuscript: Spinner, Mahan, Amrami, Marek. Approved the final version of the manuscript on behalf of all authors: Spinner. Study supervision: Spinner.

References

  • 1

    Silverman TA, Enzinger FM Fibrolipomatous hamartoma of nerve. A clinicopathologic analysis of 26 cases. Am J Surg Pathol. 1985;9(1):714.

  • 2

    Spinner RJ, Scheithauer BW, Amrami KK, Wenger DE, Hébert-Blouin MN Adipose lesions of nerve: the need for a modified classification. J Neurosurg. 2012;116(2):418431.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Mahan MA, Niederhauser BD, Amrami KK, Spinner RJ Long-term progression of lipomatosis of nerve. World Neurosurg. 2014;82(3-4):492499.

  • 4

    Marek T, Spinner RJ, Syal A, Mahan MA Strengthening the association of lipomatosis of nerve and nerve-territory overgrowth: a systematic review. J Neurosurg. 2019;132(4):12861294.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Marek T, Mahan MA, Carter JM, et al. What’s known and what’s new in adipose lesions of peripheral nerves? Acta Neurochir (Wien). 2021;163(3):835842.

  • 6

    Mahan MA, Amrami KK, Spinner RJ Fibroproliferative neuromas may occur after iatrogenic injury for lipomatosis of nerve. Neurosurgery. 2013;73(2):271281.

  • 7

    Cherqui A, Sulaiman WAR, Kline DG Resection and nerve grafting of a lipofibrohamartoma of the median nerve: case report. Neurosurgery. 2009;65(4)(suppl):A229A235.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Mahan MA, Amrami KK, Niederhauser BD, Spinner RJ Progressive nerve territory overgrowth after subtotal resection of lipomatosis of the median nerve in the palm and wrist: a case, a review and a paradigm. Acta Neurochir (Wien). 2013;155(6):11311141.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Hébert-Blouin MN, Scheithauer BW, Amrami KK, Durham SR, Spinner RJ Fibromatosis: a potential sequela of neuromuscular choristoma. J Neurosurg. 2012;116(2):399408.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Maldonado AA, Planchard RF, Jack MM, Smith BW, Carter JM, Spinner RJ Lipomatosis of nerve and neuromuscular choristoma: Two rare entities and their call for an animal model to understand and mitigate nerve-territory sequelae. World Neurosurg. 2022;159:5662.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Niederhauser BD, Spinner RJ, Jentoft ME, Everist BM, Matsumoto JM, Amrami KK Neuromuscular choristoma: characteristic magnetic resonance imaging findings and association with post-biopsy fibromatosis. Skeletal Radiol. 2013;42(4):567577.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Maldonado AA, Broski SM, Carter JM, Marek T, Howe BM, Spinner RJ Neuromuscular choristoma and circumferential nerve territory desmoid-type fibromatosis: imaging findings supporting a nerve-driven mechanism. J Neurosurg. Published online June 23, 2023. doi.org/10.3171/2023.5.JNS23323.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Kurimoto S, Jung J, Tapadia M, et al. Activation of the Wnt/β-catenin signaling cascade after traumatic nerve injury. Neuroscience. 2015;294:101108.

  • 14

    Lee CH, Wu JS, Goldsmith JD, Kung JW Lipomatosis of the sciatic nerve secondary to compression by a desmoid tumor. Skeletal Radiol. 2013;42(12):17511754.

  • 15

    Niederhauser BD, Spinner RJ, Hower BM, Amrami KK. In response to Lipomatosis of the sciatic nerve secondary to compression by a desmoid tumor. Skeletal Radiol. 2014;43(2):129.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Collapse
  • Expand
  • FIG. 1

    A–C: Interval clinical growth of the radial side of the palm, particularly the first web space and the hypertrophic scar over the past 15 years.

  • FIG. 2

    Artistic rendering showing that the sequelae of nerve resection and grafting of LN may include continued bony and soft tissue overgrowth and fibrous proliferation (with permission, Mayo Foundation, 2023) (A and B). Postcontrast coronal T1 spoiled gradient recalled echo (SPGR) MRI (C and D) shows the nodular enhancing mass-like lesions in the distal forearm and at the palm corresponding with the proximal suture line in the median nerve and the distal sutures in the digital nerves. Abnormal fatty proliferation can be seen around the nerve grafts between the nodular masses at the proximal and distal suture lines.

  • FIG. 3

    Axial T1-weighted MRI (A–H) shows the circumferential encasement of fascicles in the proximal suture line in the distal forearm sequentially from proximal to distal. In the middle, there is loss of complete architecture. Just above and below, however, there is fibrosis around the fascicular bundles. Note that LN is visible proximal to the proximal suture line.

  • FIG. 4

    Corresponding axial postcontrast T1 SGPR (spoiled gradient recalled echo) MRI (A–H) shows the enhancement.

  • FIG. 5

    Axial T1-weighted MR images (AC) show the progressive fatty overgrowth occurring in the distal palm. These provide 18-year postoperative follow-up studies since subtotal resection of the LN and nerve grafting. Asterisk indicates the radial digital nerve to the index finger; plus sign, the second common digital nerve; white arrow, third common digital nerve.

  • 1

    Silverman TA, Enzinger FM Fibrolipomatous hamartoma of nerve. A clinicopathologic analysis of 26 cases. Am J Surg Pathol. 1985;9(1):714.

  • 2

    Spinner RJ, Scheithauer BW, Amrami KK, Wenger DE, Hébert-Blouin MN Adipose lesions of nerve: the need for a modified classification. J Neurosurg. 2012;116(2):418431.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Mahan MA, Niederhauser BD, Amrami KK, Spinner RJ Long-term progression of lipomatosis of nerve. World Neurosurg. 2014;82(3-4):492499.

  • 4

    Marek T, Spinner RJ, Syal A, Mahan MA Strengthening the association of lipomatosis of nerve and nerve-territory overgrowth: a systematic review. J Neurosurg. 2019;132(4):12861294.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Marek T, Mahan MA, Carter JM, et al. What’s known and what’s new in adipose lesions of peripheral nerves? Acta Neurochir (Wien). 2021;163(3):835842.

  • 6

    Mahan MA, Amrami KK, Spinner RJ Fibroproliferative neuromas may occur after iatrogenic injury for lipomatosis of nerve. Neurosurgery. 2013;73(2):271281.

  • 7

    Cherqui A, Sulaiman WAR, Kline DG Resection and nerve grafting of a lipofibrohamartoma of the median nerve: case report. Neurosurgery. 2009;65(4)(suppl):A229A235.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Mahan MA, Amrami KK, Niederhauser BD, Spinner RJ Progressive nerve territory overgrowth after subtotal resection of lipomatosis of the median nerve in the palm and wrist: a case, a review and a paradigm. Acta Neurochir (Wien). 2013;155(6):11311141.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Hébert-Blouin MN, Scheithauer BW, Amrami KK, Durham SR, Spinner RJ Fibromatosis: a potential sequela of neuromuscular choristoma. J Neurosurg. 2012;116(2):399408.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Maldonado AA, Planchard RF, Jack MM, Smith BW, Carter JM, Spinner RJ Lipomatosis of nerve and neuromuscular choristoma: Two rare entities and their call for an animal model to understand and mitigate nerve-territory sequelae. World Neurosurg. 2022;159:5662.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Niederhauser BD, Spinner RJ, Jentoft ME, Everist BM, Matsumoto JM, Amrami KK Neuromuscular choristoma: characteristic magnetic resonance imaging findings and association with post-biopsy fibromatosis. Skeletal Radiol. 2013;42(4):567577.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Maldonado AA, Broski SM, Carter JM, Marek T, Howe BM, Spinner RJ Neuromuscular choristoma and circumferential nerve territory desmoid-type fibromatosis: imaging findings supporting a nerve-driven mechanism. J Neurosurg. Published online June 23, 2023. doi.org/10.3171/2023.5.JNS23323.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Kurimoto S, Jung J, Tapadia M, et al. Activation of the Wnt/β-catenin signaling cascade after traumatic nerve injury. Neuroscience. 2015;294:101108.

  • 14

    Lee CH, Wu JS, Goldsmith JD, Kung JW Lipomatosis of the sciatic nerve secondary to compression by a desmoid tumor. Skeletal Radiol. 2013;42(12):17511754.

  • 15

    Niederhauser BD, Spinner RJ, Hower BM, Amrami KK. In response to Lipomatosis of the sciatic nerve secondary to compression by a desmoid tumor. Skeletal Radiol. 2014;43(2):129.

    • PubMed
    • Search Google Scholar
    • Export Citation

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