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Benign peripheral nerve tumors
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Benign peripheral nerve tumors ✩ Zinon T. Kokkalis a,∗, Nikolaos A. Stavropoulos b, Andreas F. Mavrogenis c, Andreas Panagopoulos a, Panayotis N. Soucacos d a
University of Patras, School of Medicine, University Hospital of Patras, Department of Orthopaedics, Rio-Patras, Greece Second Department of Orthopaedics, National and Kapodistrian University of Athens, School of Medicine, Konstantopouleio General Hospital, Athens, Greece c First Department of Orthopaedics, National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Athens, Greece d “Panayotis N. Soucacos” Orthopaedic Research & Education Center (OREC), National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Athens, Greece b
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Peripheral nerves Benign tumors Neoplasms Non-neoplastic lesions
a b s t r a c t Benign peripheral nerve tumors encompass a wide range of neoplasms and non-neoplastic tumor like lesions. Some of these lesions if not encountered in the setting of genetic syndromes, are occurring sporadically. The principles of oncology should be respectfully followed in every step of diagnostic approach and surgical management. Albeit, classified as benign, some of them do have different level of malignant potential, thus the treating physicians should be aware of that to avoid possible pitfalls with devastating outcomes. This article reviews the most common benign peripheral nerve tumors discussing the clinicopathological findings, imaging appearance and the current trend in their approach. © 2019 Elsevier Ltd. All rights reserved.
Introduction
Diagnostic approach
Benign Peripheral Nerve Tumors (BPNT) is a heterogeneous cohort consisting of non-neoplastic tumoral masses, neoplastic nonneural sheath tumours and neoplasms of nerve sheaths. The variety a clinical importance yields a great interest to draw the interest to their existence. Literature presents many cases of mainly malignant peripheral nerve tumors with great interest as well, unfolding and revealing that way the paramount importance of the knowledge of the nerve tumors in the daily clinical practise. Data on benign peripheral nerve tumors though are not so widely published in comparison to malignant ones mainly mirroring the difference in thein biological behaviour. Kim et al. in 2005, published a series of peripheral non-neural sheath nerve tumor [1] and later in 2016, Mortano et al. focused on the prognostic factors on a series of 150 patients with adequate follow up data that had been operated for peripheral nerve tumors [2].This article reviews the most common BPNTs and discusses the clinicopathological findings, imaging appearance and the current trend in the management for these. The purpose of our study is to raise awareness and keep suspicion of treating physician’s high on that type of tumors.
Upon presentation, patients should be carefully examined including full medical history with specific interest in any signs that could be directly correlated to their symptoms. Specific questions should be addressed and notes acquired on when was the tumor firstly noted, any possible change in size and if so, the rate of the growth; any possible b-symptoms that could be attributed to the primary diagnosis if any. Tumor related family history is of interest to know as well. Furthermore, it is important to know if there are specific conditions yielding the tumor symptoms. Following that, a thorough clinical examination starting from observation of the tumor should be performed documenting the findings. Regional lymph nodes should be assessed routinely in any type of tumor regardless any specific features. Given that the BPNTs are benign behaving tumoral masses, the majority of the clinical symptomatology is demonstrated by findings arising either from the surrounding structures mainly direct related to the size of the mass, noted as mass effect or from the mass itself through intraneural involvement or tumor invasion of the nerve [3]. Following that, patients present with either neurological findings or local mass induced symptoms [4]. Albeit laboratory findings are of paramount importance in the clinical practise, in BPNTs and once the diagnosis has been established, they can be acquired to evaluate the patient’s overall medical status. Contrary to that, imaging findings including diagnostic ultrasound (U/S) and magnetic resonance (MRI) are the first-
✩ This paper is part of a Supplement supported by the European Federation of Societies of Microsurgery (EFSM) and the Serbian Society for Reconstructive Microsurgery (SSRM). ∗ Corresponding author at: University Hospital of Patras, Department of Orthopaedics, Papanikolaou 1, 26504 Rio-Patras, Greece. E-mail address: [email protected] (Z.T. Kokkalis).
https://doi.org/10.1016/j.injury.2019.10.054 0020-1383/© 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Z.T. Kokkalis, N.A. Stavropoulos and A.F. Mavrogenis et al., Benign peripheral nerve tumors, Injury, https: //doi.org/10.1016/j.injury.2019.10.054
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choice modalities in the treating arsenal of such tumors. Initially to establish an idea of the shape, integrity, matrix and size of the tumor with the U/S, followed by more detailed findings and features in the MR imaging. Coming at the end but of the paramount importance is the tissue biopsy. In the cases of peripheral nerve tumors, biopsy is indicated when a malignant tumor is suspected, and tissue biopsy is mandatory to determine the definite management. The results of the tissue biopsy depend on the sample that will be acquired, and this fact reveals the importance of the procedure that could be performed either closed or open depending on the many factors though [5–8]. Irrespective that, the oncological principles of biopsy that have been widely described and must be followed include that the biopsy must be undertaken through one compartment, ensuring that the tissue planes are not violated with adequate hemostasis and by an extensile approach that could be used for the resection of the tumor [9,10]. No need to mention that the approach to any oncological case is a team approach performed by experienced and dedicated treating physicians. Pre-operative Nerve Conducting Tests (NCT) are useful only in the identification of the nerve assisting the thorough clinical examination that as it has been aforementioned should have been already done [11]. Contrary to that, intra-operative electrophysiology monitoring is of great importance to minimize the residual neurologic deficit [11,12]. Benign neoplasms of nerve sheaths or nerve sheath tumors Schwannoma Schwannomas are sporadically occurring nerve sheath tumors, unless associated with neurofibromatosis syndrome, of unknown aetiology [13] but of Schwann cell origin. They arise from Schwann cells and they are encapsulated biphasic sheath tumors of two components, Antoni A area of highly ordered cellular component and Antoni B area of loose myxoid component. The component percentage of these two areas varies. While affecting all ages, they peak in the fourth to sixth decade [13]. In a population based analysis performed by Antinheimo et al., around 90% of schwannomas were sporadic, 3% in patients with Neurofibromatosis-2 (NF-2), 2% in patients with schwannomatosis of whom there was small percent (2 patients in 11 totally) with familiar schwannomatosis, 5% in association with multiple meningiomas in patients with or without NF-2 (1% with and 4% without) [14,15]. Multiple Schwannomas are not only noticed in NF-2 syndrome but also in Gorlin-Koutlas as well [13]. Immunostaining for S-100 protein contributes to the differential from neurofibroma. Schwannomas are benign, albeit the minimal cases of malignant transformations that have been reported in the literature [16–19]. Neurofibromatosis is a genetically disease with two forms; the common peripheral form known as neurofibromatosis-1 (NF-1) and the less common neurofibromatosis −2 (NF-2). Schwannomas are slow growing tumors often present asymptomatic for several year before the diagnosis localized commonly in peripheral nerves of the skin and subcutaneous tissues of the head, neck or the flexor surfaces of the extremities [11,13]. Spinal schwannoma is relative rare [20]. Neurologic symptoms and pain are noted predominately in sized tumors resulting from the mass effect. Given that the tumor arise from the sheath, it is covered by a capsule consisted with epineurium and nerve fibers [15]. On MRI, schwannomas have an intermediate signal intensity on T1-weighted imaging, while demonstrating bright signal on T2weithed imaging [21]. It is of importance to carefully identify the incoming and outcoming nerve fibers, fascicles while performing surgical resection of the schwannoma as it has been previously mentioned in the
literature [22] in order to minimize the residual nerve deficit. A case of radial nerve Schwannoma is presented in Fig. 1. Ancient schwannoma Deep seated tumors with degenerative features like focal cystic component, calcification, necrosis and hemorrhage. The term has been initially introduced by Ackerman and Taylor in the 50 s [23]. Cases of retroperitoneal location have been reported albeit infrequent location [24]. Cellular schwannoma Cellular Schwannoma (CS) is a variant characterized by predominantly Antoni A tissue without Verocay bodies. These tumors are mainly located at paravertebral sites, mediastinum, retroperitoneum and pelvis [13] with only around 25% in extremities [15]. CS was initially treated with scepticism and thought that in fact were low grade Malignant Peripheral Nerve Sheath Tumors (MPNST) but as more literature was published the benign behaviour was reassured [25–27]. Plexiform schwannoma (PSch) Plexiform Schwannomas are rare, but they can even involve brachial plexus and thus can be diagnosed early. Unlike plexiform neurofibromas, they do not display malignant features. Melanotic schwannoma Melanotic Schannomas unlike other variants of Schwannomas, can progress to malignancy. The tumor arises from the sympathetic nervous system, is a distinctive neoplasm of adult life identified by variably melanin-producing Schwann cells [13,15,28–31]. Psammomatous melanotic schwannomas are characterized by psammoma bodies that are round shaped, laminated bodies [28–31]. Neurofibroma Neurofibromas are the most common PNSTs occurring sporadically unless associated with Neurofibromatosis type 1 (NF-1) [13]. They are consisted of Schwann cells, perineurial-like cells, and fibroblasts, mast cells and myelinated and unmyelinated axons embedded in matrix [13,32]. The World Health Organization (WHO) has defined five subtypes of neurofibroma. The most common one that is the localized subcutaneous occurring in the dermis and subcutaneous tissues, 90% seen sporadic and 10% in NF-1;the diffuse cutaneous also in the dermis and subcutaneous tissues; the localized intraneural encountered in cranial, spinal or autonomic nerves either sporadically or associated with NF-1. Plexiform and Massive soft tissue are the last two subtypes that are exclusively associated with NF-1 [33]. Between these subtypes, only the localized cutaneous has no malignant potential, while for the rest, it varies with the plexiform to have the highest [33]. Certain criteria have also been defined to establish the diagnosis of NF-1 [34] and NF-2 as well [35,36] Imaging can be helpful for the monitoring and observation of the appearance and the characteristics of the tumors during the clinical course. Presence of the so called “target sign” on the T2weithed images that represents a central hypointense area in the tumoral mass presumably attributed to the collagen and fibrous component, is highly suggestive but not pathognomonic of the neurofibroma [37]. Furthermore, the “reverse target sign” may be noticed on the T1-weighted images characterized by enhancement of the central component [37]. The role of positron emission tomography is of paramount importance as well in the evaluation and decision making in these cases where all the nodular lesion have to be monitored by the treating physician [38]. Treatment is dependent on the symptoms and the clinical characteristics of the tumors. If the patient is symptomatic and the diagnosis is not certain, the option of surgical resection becomes the
Please cite this article as: Z.T. Kokkalis, N.A. Stavropoulos and A.F. Mavrogenis et al., Benign peripheral nerve tumors, Injury, https: //doi.org/10.1016/j.injury.2019.10.054
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Fig. 1. A 19-year-old female presented to the Outpatient’s Clinic complaining of pain in her right forearm. Following a thorough clinical examination, an MRI was obtained to confirm the clinical suspicion of a radial nerve related tumor. MRI demonstrated a mass between the lateral and medial head of the triceps (a) roughly measured 20 × 14 × 26 mm arising from the radial nerve. After having discussed the risks and benefits of the procedure, the patient was consented for resection that was performed through a longitudinal approach (b). Intraoperative findings revealed a well circumcised and encapsulated mass (c and d) along the course of the radial nerve. The mass was fully resected after having identified the incoming and outcoming arising facile of the nerve (e and f). The Pathology report confirmed was consistent with schwannoma. Post-operatively the patient was doing fine with no residual neurologic deficit. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
first in option’s line. In the cases of plexiform neurofibromas, systematic therapies had been implemented displaying stabilization of the mass [39,40]. Outcome though is highly correlated with factors such as location, extent and involvement of the tumor and pre-operative nerve functional status of the patient. A great issue that has to be addressed and has been of paramount importance is the incidence of malignant transformation. Albeit literature is not very clear on the exact incidence, there is consensus that there is a lifetime risk in individuals with NF-1 for malignant transformation [41]. Perineurioma Perineurioma is a nerve sheath tumor comprised entirely of perineural cells. Lazarus and Trombetta firstly described them based on ultrasound findings [42]. Perineuriomas are rare tumors with limited cases been published in the literature. They peak in middle-aged adults with slightly preferring females [43] and may be presented either as intraneural or extraneural, as sclerosing and reticular. Intraneural perineuriomas were termed as localized hypertrophic neuropathy but based on their characteristic appearance of the perineural cells in the epithelial membrane antigen (EMA) and S-100 protein immunostaining in cross section imaging, there were cat-
egorized as a true neoplastic lesion [15,44]. The intraneural perineurioma displays benign behaviour. Clinically muscle weakness or nerve type symptoms are driving the attention to the existence of the tumors. No specific guidelines for their treatment have been reported. The extraneural (soft tissue) perineurioma is encountered more often in comparison to the intraneural one, even though both of them are uncommon [43]. Equally affecting females and males, the soft tissue perineurioma range in size with average size of 4 cm [15,43]. Treatment management follows the same principles as the intraneural keeping in mind that albeit some cases of recurrence and atypical features have been reported, perineuriomas are benign tumors. The sclerosing perineurioma is an unusual variant as well that affects exclusively the hand [15,45]. Typically presented as painless mass, no recurrence was documented following surgical resection in the cohort of Fetsch et al. [45]. Epithelioid lesions are part of the differential diagnosis. Hybrid nerve sheath tumor Although Hybrid Nerve Sheath Tumors (HNST) have been recognised and described years ago, they have been included in the WHO classification in 2013 and 2016 [13,46,47]. HNST display
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combined features and characteristics of more than one type of PNSTs. The most common type is of schwannoma/perineurioma that occurs sporadically while the neurofibroma/schwannoma is associated with patients in neurofibromatosis [47]. Treating physicians should be aware that Hybrid PNSTs are associated with tumoral syndromes, 25% of patients with NF-2 and while the percentage is higher in patients with NF-1 have neoplasms with hybrid features [47–49]. Nerve sheath myxomas (NSM) - Dermal Nerve sheath myxomas The tumor has been in the past referred as myxoid variant of neurothekeoma but recently has been termed as a benign tumor completely different from neurothekeoma and these two entities are totally unrelated [13,50]. Neurothekeoma has been suggested to be a variant in the spectrum of fibrohistiotic tumors [51]. The tumor is encountered predominantly in the dermis and subdermis layer, other locations like dorsal paravertebral space have been rarely reported [52]. NSM principally arise in the extremities with the fingers accounting for the about 35% of he cases [50]. Literature review has revealed cases in patients ranging between few months and 84 years old [52,53]. Clinically NSMs present as small, slowly growing masses often asymptomatic other than diffuse pain in the involved area. No specific guidelines on the treatment approach have been published. In a cohort published by Fetsch et al. almost half of the patient that had undergone surgical resection, faced one or more incidences of recurrence but with no evidence of malignancy whatsoever [50]. Granular cell tumor Granular Cell Tumors are small in size benign tumors categorized among the benign nerve sheath tumors [54,55]. Typically involving the skin, soft tissue of the head, neck and the viscera a well; cases of extremities involvement have been reported [56– 58]. Resection and nerve grafting if needed should be suggested depending on the symptoms. Recurrence has been described on approximately 8% [57,58]
Fig. 2. A 5-year-old female presented with congenital macrodactyly. The patient underwent partial resection of the dystrophic fat tissue through a palmar approach (a). The median nerve and the digital nerves were hypertrophic (as shown at the red vessel loops) as typical Lipofibromatous Hamartoma, and nerve decompression was only performed (b). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Benign neoplasms of non-nerve sheaths origin or benign non-nerve sheath tumors (BNNST) of peripheral nerves Lipofibromatous hamartoma of the nerves Lipofibromatous Hamartoma of the Nerves (LHN) or neural fibrolipoma is an infrequent peripheral nerve tumor mostly involving the median nerve and its digital nerves [8]. It has been reported to be correlated with macrodactyly or macrodystrophia lipomatosa at birth [13,62,63]. LHN has a characteristic “cable-like” appearance on T1 and T2-weighted images [62–64]. Due to fact that the neoplasm is “imbedded” within the nerve fibers, it is difficult to be dissected in tumor free margins, therefor excision is rarely recommended [64]. Symptom based treatment management is suggested in terms of nerve decompression [65]. A case of LHN is presented in Fig. 2.
Benign triton tumor
Desmoid-Type fibromatosis
Benign Triton Tumor (BTT)s are neoplasms of neural and mature skeletal muscle cells with limited number published in the literature termed otherwise as hamartomata [13,59]. By predilection involving large peripheral nerves or plexi like sciatic nerve and brachial plexus most commonly in infancy or childhood [13,59]. Peripheral neuropathy symptoms when present lead the diagnostic approach. The principles of surgical resection apply here as well.
Desmoid-Type Fibromatosis (DTF) involving peripheral nerves is an aggressive neoplasia characterized by infiltrative but benign fibroblasts. These tumors due to the fibrous tissue behave as a firm mass. Cases of DTF involving peripheral nerves have been sporadically reported in the literature [66,67]. Desmoid Tumors are often symptomatic but there is no consensus in the literature for the optimal treatment; thus, each case should be discussed on a customized patient-specific way.
Nerve sheath ganglions – intraneural ganglions Hemangioblastoma Literature review revealed cases of nerve sheath ganglia (NSG) involving peripheral nerves [60,61]. Ganglia represent most likely a degenerative process than a true neoplasm. Nerve Sheath Ganglia are cystic formations in the epineurium of the nerves and they contain clear fluid of jelly-like consistency. NSG mostly involve the peroneal nerve while case of other peripheral nerve involvement have been reported [15,60,61]. The nerve gets the appearance of focal swelling that corresponds to the cystic formation. Symptoms derive from the compression effect generated by the cyst. Either described as acute or diffuse, radiating pain and deficit should be taken into consideration in the decision making process of the treatment management. Options include local resection while cyst decompression is an accepted alternative in the case that the nerve integrity is at risk [15,60,61].
Hemangioblastoma is a rare begin tumor with approximately 25% of them encountered in the Von Hippel – Lindau (VHL) syndrome [68]. Albeit the vast majority arises in the Central Nervous System, cases of peripheral sites have been reported [68–70]. Clinically, patients present with progressive neurological symptoms resulting from progressive deficit. Surgical resection with clear margins appears to be the treatment of choice [68]. Ganglion cyst – extraneural ganglion cysts Ganglion Cysts as it has aforementioned can be either intraneural or extraneural. Many theories have described the possible aetiology of the extraneural ones. Synovial hernias, trauma or
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Fig. 3. A 29-year-old male presented to the Outpatient’s Clinic complaining of pain his right knee arising at the level of the lateral head of the gastrocnemius. Following a thorough clinical examination, an MRI was obtained demonstrating a cystic fluid-like mass in close proximity to the common peroneal nerve yielding symptoms from nerve compression (a and b). The mass was not suspicious for any malignant component as it was homogeneous with no invasive behaviour to the surrounding tissue envelope. After having discussed the risks and benefits of the procedure, the patient was consented for resection through a direct approach over the area of interest in an extensile way (c). Intraoperative, the cystic formation was confirmed (d) and the decision was to evacuate the cyst, by decompression of the jelly-like component (e). The common peroneal nerve was intact. Pathology report was consistent with ganglion cyst. The postoperative period was uneventful and the patient is free of any clinical worrisome symptoms 18 months later.
mucoid degeneration are among the most commonly suggested [8,71]. Ganglia account for the 50–70% of the tumors of the hand [8] while the other frequent area is around the common peroneal nerve. Rawal et hypothesized that the proximal tibiofibular joint is the origin of the peroneal ganglia [72,73]. Symptoms originate secondary to the pressure effect on the nerve. If the symptoms can be tolerated by the patient, then observation and monitoring is a choice within the treatment arsenal as there have been reported cases in which ganglia spontaneously disappeared in about 40% of them [8,74,75]. Other than monitoring, aspiration or complete surgical resection of the cyst are the other options. It is an importance to keep in mind that the recurrence rate is relatively high [76]. A case of extraneural Ganglion Cyst is presented in Fig. 3. Traumatic neuromas Traumatic Neuromas (TN) are typical benign tumors that develop post neurotmesis resulting from the lack of endoneurium tube during nerve regeneration. Axonal regrowth, development and distribution seems to be the key role in the TN formation [77]. Dysesthesia and Traumatic Neuropathic Pain are among the most discomforting symptoms that have to be addressed while neuromas as a tumoral mass itself appears to be firm occasional painful nodule [78]. Several treatment modalities have been proposed with raging outcomes [77–79]. A diagnostic dilemma appears when the initial surgery was oncological mandated and a new tumoral formation is noted in the surgical field in proximity with the nerve during the follow up. This case scenario has been most of the
times in the agenda of Tumor Boards Summits raising the question of tumor recurrence over neuroma formation. Tumor-like lesions Neuritis ossificans or intraneural heterotopic ossification Limited literature is available for Intraneural Heterotopic Ossification (IHO). Woltman et al. in 1946 followed by Catalano et al. in several years later in 1992 were among the first to have reported a case of IHO or neuritis ossificans [80,81]. Not typically encountered lesion is characterized by apposition of fibrovascular tissue with an intermediate zone of osteoid and a periphery of ossification microscopically [82–84]. Trauma is proposed as a risk factor [82,83]. Symptoms of progressive muscular weakness, painful mononeuropathy, focal swelling alongside the course of involved nerve should be assessed in the clinical examination [82,84]. Biopsy should be considered when possibility of malignancy is suspected as specific types of osteoblastic sarcomas exist. Management of IHO is symptom oriented and many factors should be taken into consideration in the setting of prevention by possible iatrogenic nerve damage. Declaration of Competing Interest All authors report no conflict of interest in relation to this study.
Please cite this article as: Z.T. Kokkalis, N.A. Stavropoulos and A.F. Mavrogenis et al., Benign peripheral nerve tumors, Injury, https: //doi.org/10.1016/j.injury.2019.10.054
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[72] Rawal A, Ratnam KR, Yin Q, Sinopidis C, Frostick SP. Compression neuropathy of common peroneal nerve caused by an extraneural ganglion: a report of two cases. Microsurgery 2004;24(1):63–6. [73] Nikolopoulos D, Safos G, Sergides N, Safos P. Deep peroneal nerve palsy caused by an extraneural ganglion cyst: a rare case. Case Rep Orthop 2015;2015:861697. [74] Zachariae L, Vibe-Hansen H. Ganglia. recurrence rate elucidated by a follow-up of 347 operated cases. Acta Chir Scand 1973;139(7):625–8. [75] McEVEDY BV. The simple ganglion: a review of modes of treatment and an explanation of the frequent failures of surgery. Lancet 1954;266(6803):135–6. [76] Thornburg LE. Ganglions of the hand and wrist. J Am Acad Orthop Surg 1999;7(4):231–8. [77] Oliveira KMC, Pindur L, Han Z, Bhavsar MB, Barker JH, Leppik L. Time course of traumatic neuroma development. PLoS ONE 2018;13(7):e0200548. [78] Yao C, Zhou X, Zhao B, Sun C, Poonit K, Yan H. Treatments of traumatic neuropathic pain: a systematic review. Oncotarget 2017;8(34):57670–9. [79] Kang J, Yang P, Zang Q, He X. Traumatic neuroma of the superficial peroneal nerve in a patient: a case report and review of the literature. World J Surg Oncol 2016;14(1):242. [80] Woltman HW, Adson AW, et al. Neuritis ossificans with osteogenic sarcoma in brachial plexus following trauma; report of case. J Lancet 1946;66(11):372–6. [81] Catalano F, Fanfani F, Pagliei A, Taccardo G. [A case of primary intraneural ossification of the ulnar nerve]. Ann Chir Main Memb Super 1992;11(2):157–62 French. [82] Muzaffar N, Ahmad N, Bhat A, Shah N. Neuritis ossificans of the radial nerve. Orthopedics 2012;35(4):e589–91. [83] McCarthy EF, Sundaram M. Heterotopic ossification: a review. Skeletal Radiol 2005;34(10):609–19. [84] George DH, Scheithauer BW, Spinner RJ, Buchler U, Cronin TE, Reedy MT, et al. Heterotopic ossification of peripheral nerve (“neuritis ossificans”): report of two cases. Neurosurgery 2002;51(1):244–6.
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Benign peripheral nerve tumors ✩ Zinon T. Kokkalis a,∗, Nikolaos A. Stavropoulos b, Andreas F. Mavrogenis c, Andreas Panagopoulos a, Panayotis N. Soucacos d a
University of Patras, School of Medicine, University Hospital of Patras, Department of Orthopaedics, Rio-Patras, Greece Second Department of Orthopaedics, National and Kapodistrian University of Athens, School of Medicine, Konstantopouleio General Hospital, Athens, Greece c First Department of Orthopaedics, National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Athens, Greece d “Panayotis N. Soucacos” Orthopaedic Research & Education Center (OREC), National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Athens, Greece b
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Peripheral nerves Benign tumors Neoplasms Non-neoplastic lesions
a b s t r a c t Benign peripheral nerve tumors encompass a wide range of neoplasms and non-neoplastic tumor like lesions. Some of these lesions if not encountered in the setting of genetic syndromes, are occurring sporadically. The principles of oncology should be respectfully followed in every step of diagnostic approach and surgical management. Albeit, classified as benign, some of them do have different level of malignant potential, thus the treating physicians should be aware of that to avoid possible pitfalls with devastating outcomes. This article reviews the most common benign peripheral nerve tumors discussing the clinicopathological findings, imaging appearance and the current trend in their approach. © 2019 Elsevier Ltd. All rights reserved.
Introduction
Diagnostic approach
Benign Peripheral Nerve Tumors (BPNT) is a heterogeneous cohort consisting of non-neoplastic tumoral masses, neoplastic nonneural sheath tumours and neoplasms of nerve sheaths. The variety a clinical importance yields a great interest to draw the interest to their existence. Literature presents many cases of mainly malignant peripheral nerve tumors with great interest as well, unfolding and revealing that way the paramount importance of the knowledge of the nerve tumors in the daily clinical practise. Data on benign peripheral nerve tumors though are not so widely published in comparison to malignant ones mainly mirroring the difference in thein biological behaviour. Kim et al. in 2005, published a series of peripheral non-neural sheath nerve tumor [1] and later in 2016, Mortano et al. focused on the prognostic factors on a series of 150 patients with adequate follow up data that had been operated for peripheral nerve tumors [2].This article reviews the most common BPNTs and discusses the clinicopathological findings, imaging appearance and the current trend in the management for these. The purpose of our study is to raise awareness and keep suspicion of treating physician’s high on that type of tumors.
Upon presentation, patients should be carefully examined including full medical history with specific interest in any signs that could be directly correlated to their symptoms. Specific questions should be addressed and notes acquired on when was the tumor firstly noted, any possible change in size and if so, the rate of the growth; any possible b-symptoms that could be attributed to the primary diagnosis if any. Tumor related family history is of interest to know as well. Furthermore, it is important to know if there are specific conditions yielding the tumor symptoms. Following that, a thorough clinical examination starting from observation of the tumor should be performed documenting the findings. Regional lymph nodes should be assessed routinely in any type of tumor regardless any specific features. Given that the BPNTs are benign behaving tumoral masses, the majority of the clinical symptomatology is demonstrated by findings arising either from the surrounding structures mainly direct related to the size of the mass, noted as mass effect or from the mass itself through intraneural involvement or tumor invasion of the nerve [3]. Following that, patients present with either neurological findings or local mass induced symptoms [4]. Albeit laboratory findings are of paramount importance in the clinical practise, in BPNTs and once the diagnosis has been established, they can be acquired to evaluate the patient’s overall medical status. Contrary to that, imaging findings including diagnostic ultrasound (U/S) and magnetic resonance (MRI) are the first-
✩ This paper is part of a Supplement supported by the European Federation of Societies of Microsurgery (EFSM) and the Serbian Society for Reconstructive Microsurgery (SSRM). ∗ Corresponding author at: University Hospital of Patras, Department of Orthopaedics, Papanikolaou 1, 26504 Rio-Patras, Greece. E-mail address: [email protected] (Z.T. Kokkalis).
https://doi.org/10.1016/j.injury.2019.10.054 0020-1383/© 2019 Elsevier Ltd. All rights reserved.
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choice modalities in the treating arsenal of such tumors. Initially to establish an idea of the shape, integrity, matrix and size of the tumor with the U/S, followed by more detailed findings and features in the MR imaging. Coming at the end but of the paramount importance is the tissue biopsy. In the cases of peripheral nerve tumors, biopsy is indicated when a malignant tumor is suspected, and tissue biopsy is mandatory to determine the definite management. The results of the tissue biopsy depend on the sample that will be acquired, and this fact reveals the importance of the procedure that could be performed either closed or open depending on the many factors though [5–8]. Irrespective that, the oncological principles of biopsy that have been widely described and must be followed include that the biopsy must be undertaken through one compartment, ensuring that the tissue planes are not violated with adequate hemostasis and by an extensile approach that could be used for the resection of the tumor [9,10]. No need to mention that the approach to any oncological case is a team approach performed by experienced and dedicated treating physicians. Pre-operative Nerve Conducting Tests (NCT) are useful only in the identification of the nerve assisting the thorough clinical examination that as it has been aforementioned should have been already done [11]. Contrary to that, intra-operative electrophysiology monitoring is of great importance to minimize the residual neurologic deficit [11,12]. Benign neoplasms of nerve sheaths or nerve sheath tumors Schwannoma Schwannomas are sporadically occurring nerve sheath tumors, unless associated with neurofibromatosis syndrome, of unknown aetiology [13] but of Schwann cell origin. They arise from Schwann cells and they are encapsulated biphasic sheath tumors of two components, Antoni A area of highly ordered cellular component and Antoni B area of loose myxoid component. The component percentage of these two areas varies. While affecting all ages, they peak in the fourth to sixth decade [13]. In a population based analysis performed by Antinheimo et al., around 90% of schwannomas were sporadic, 3% in patients with Neurofibromatosis-2 (NF-2), 2% in patients with schwannomatosis of whom there was small percent (2 patients in 11 totally) with familiar schwannomatosis, 5% in association with multiple meningiomas in patients with or without NF-2 (1% with and 4% without) [14,15]. Multiple Schwannomas are not only noticed in NF-2 syndrome but also in Gorlin-Koutlas as well [13]. Immunostaining for S-100 protein contributes to the differential from neurofibroma. Schwannomas are benign, albeit the minimal cases of malignant transformations that have been reported in the literature [16–19]. Neurofibromatosis is a genetically disease with two forms; the common peripheral form known as neurofibromatosis-1 (NF-1) and the less common neurofibromatosis −2 (NF-2). Schwannomas are slow growing tumors often present asymptomatic for several year before the diagnosis localized commonly in peripheral nerves of the skin and subcutaneous tissues of the head, neck or the flexor surfaces of the extremities [11,13]. Spinal schwannoma is relative rare [20]. Neurologic symptoms and pain are noted predominately in sized tumors resulting from the mass effect. Given that the tumor arise from the sheath, it is covered by a capsule consisted with epineurium and nerve fibers [15]. On MRI, schwannomas have an intermediate signal intensity on T1-weighted imaging, while demonstrating bright signal on T2weithed imaging [21]. It is of importance to carefully identify the incoming and outcoming nerve fibers, fascicles while performing surgical resection of the schwannoma as it has been previously mentioned in the
literature [22] in order to minimize the residual nerve deficit. A case of radial nerve Schwannoma is presented in Fig. 1. Ancient schwannoma Deep seated tumors with degenerative features like focal cystic component, calcification, necrosis and hemorrhage. The term has been initially introduced by Ackerman and Taylor in the 50 s [23]. Cases of retroperitoneal location have been reported albeit infrequent location [24]. Cellular schwannoma Cellular Schwannoma (CS) is a variant characterized by predominantly Antoni A tissue without Verocay bodies. These tumors are mainly located at paravertebral sites, mediastinum, retroperitoneum and pelvis [13] with only around 25% in extremities [15]. CS was initially treated with scepticism and thought that in fact were low grade Malignant Peripheral Nerve Sheath Tumors (MPNST) but as more literature was published the benign behaviour was reassured [25–27]. Plexiform schwannoma (PSch) Plexiform Schwannomas are rare, but they can even involve brachial plexus and thus can be diagnosed early. Unlike plexiform neurofibromas, they do not display malignant features. Melanotic schwannoma Melanotic Schannomas unlike other variants of Schwannomas, can progress to malignancy. The tumor arises from the sympathetic nervous system, is a distinctive neoplasm of adult life identified by variably melanin-producing Schwann cells [13,15,28–31]. Psammomatous melanotic schwannomas are characterized by psammoma bodies that are round shaped, laminated bodies [28–31]. Neurofibroma Neurofibromas are the most common PNSTs occurring sporadically unless associated with Neurofibromatosis type 1 (NF-1) [13]. They are consisted of Schwann cells, perineurial-like cells, and fibroblasts, mast cells and myelinated and unmyelinated axons embedded in matrix [13,32]. The World Health Organization (WHO) has defined five subtypes of neurofibroma. The most common one that is the localized subcutaneous occurring in the dermis and subcutaneous tissues, 90% seen sporadic and 10% in NF-1;the diffuse cutaneous also in the dermis and subcutaneous tissues; the localized intraneural encountered in cranial, spinal or autonomic nerves either sporadically or associated with NF-1. Plexiform and Massive soft tissue are the last two subtypes that are exclusively associated with NF-1 [33]. Between these subtypes, only the localized cutaneous has no malignant potential, while for the rest, it varies with the plexiform to have the highest [33]. Certain criteria have also been defined to establish the diagnosis of NF-1 [34] and NF-2 as well [35,36] Imaging can be helpful for the monitoring and observation of the appearance and the characteristics of the tumors during the clinical course. Presence of the so called “target sign” on the T2weithed images that represents a central hypointense area in the tumoral mass presumably attributed to the collagen and fibrous component, is highly suggestive but not pathognomonic of the neurofibroma [37]. Furthermore, the “reverse target sign” may be noticed on the T1-weighted images characterized by enhancement of the central component [37]. The role of positron emission tomography is of paramount importance as well in the evaluation and decision making in these cases where all the nodular lesion have to be monitored by the treating physician [38]. Treatment is dependent on the symptoms and the clinical characteristics of the tumors. If the patient is symptomatic and the diagnosis is not certain, the option of surgical resection becomes the
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Fig. 1. A 19-year-old female presented to the Outpatient’s Clinic complaining of pain in her right forearm. Following a thorough clinical examination, an MRI was obtained to confirm the clinical suspicion of a radial nerve related tumor. MRI demonstrated a mass between the lateral and medial head of the triceps (a) roughly measured 20 × 14 × 26 mm arising from the radial nerve. After having discussed the risks and benefits of the procedure, the patient was consented for resection that was performed through a longitudinal approach (b). Intraoperative findings revealed a well circumcised and encapsulated mass (c and d) along the course of the radial nerve. The mass was fully resected after having identified the incoming and outcoming arising facile of the nerve (e and f). The Pathology report confirmed was consistent with schwannoma. Post-operatively the patient was doing fine with no residual neurologic deficit. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
first in option’s line. In the cases of plexiform neurofibromas, systematic therapies had been implemented displaying stabilization of the mass [39,40]. Outcome though is highly correlated with factors such as location, extent and involvement of the tumor and pre-operative nerve functional status of the patient. A great issue that has to be addressed and has been of paramount importance is the incidence of malignant transformation. Albeit literature is not very clear on the exact incidence, there is consensus that there is a lifetime risk in individuals with NF-1 for malignant transformation [41]. Perineurioma Perineurioma is a nerve sheath tumor comprised entirely of perineural cells. Lazarus and Trombetta firstly described them based on ultrasound findings [42]. Perineuriomas are rare tumors with limited cases been published in the literature. They peak in middle-aged adults with slightly preferring females [43] and may be presented either as intraneural or extraneural, as sclerosing and reticular. Intraneural perineuriomas were termed as localized hypertrophic neuropathy but based on their characteristic appearance of the perineural cells in the epithelial membrane antigen (EMA) and S-100 protein immunostaining in cross section imaging, there were cat-
egorized as a true neoplastic lesion [15,44]. The intraneural perineurioma displays benign behaviour. Clinically muscle weakness or nerve type symptoms are driving the attention to the existence of the tumors. No specific guidelines for their treatment have been reported. The extraneural (soft tissue) perineurioma is encountered more often in comparison to the intraneural one, even though both of them are uncommon [43]. Equally affecting females and males, the soft tissue perineurioma range in size with average size of 4 cm [15,43]. Treatment management follows the same principles as the intraneural keeping in mind that albeit some cases of recurrence and atypical features have been reported, perineuriomas are benign tumors. The sclerosing perineurioma is an unusual variant as well that affects exclusively the hand [15,45]. Typically presented as painless mass, no recurrence was documented following surgical resection in the cohort of Fetsch et al. [45]. Epithelioid lesions are part of the differential diagnosis. Hybrid nerve sheath tumor Although Hybrid Nerve Sheath Tumors (HNST) have been recognised and described years ago, they have been included in the WHO classification in 2013 and 2016 [13,46,47]. HNST display
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combined features and characteristics of more than one type of PNSTs. The most common type is of schwannoma/perineurioma that occurs sporadically while the neurofibroma/schwannoma is associated with patients in neurofibromatosis [47]. Treating physicians should be aware that Hybrid PNSTs are associated with tumoral syndromes, 25% of patients with NF-2 and while the percentage is higher in patients with NF-1 have neoplasms with hybrid features [47–49]. Nerve sheath myxomas (NSM) - Dermal Nerve sheath myxomas The tumor has been in the past referred as myxoid variant of neurothekeoma but recently has been termed as a benign tumor completely different from neurothekeoma and these two entities are totally unrelated [13,50]. Neurothekeoma has been suggested to be a variant in the spectrum of fibrohistiotic tumors [51]. The tumor is encountered predominantly in the dermis and subdermis layer, other locations like dorsal paravertebral space have been rarely reported [52]. NSM principally arise in the extremities with the fingers accounting for the about 35% of he cases [50]. Literature review has revealed cases in patients ranging between few months and 84 years old [52,53]. Clinically NSMs present as small, slowly growing masses often asymptomatic other than diffuse pain in the involved area. No specific guidelines on the treatment approach have been published. In a cohort published by Fetsch et al. almost half of the patient that had undergone surgical resection, faced one or more incidences of recurrence but with no evidence of malignancy whatsoever [50]. Granular cell tumor Granular Cell Tumors are small in size benign tumors categorized among the benign nerve sheath tumors [54,55]. Typically involving the skin, soft tissue of the head, neck and the viscera a well; cases of extremities involvement have been reported [56– 58]. Resection and nerve grafting if needed should be suggested depending on the symptoms. Recurrence has been described on approximately 8% [57,58]
Fig. 2. A 5-year-old female presented with congenital macrodactyly. The patient underwent partial resection of the dystrophic fat tissue through a palmar approach (a). The median nerve and the digital nerves were hypertrophic (as shown at the red vessel loops) as typical Lipofibromatous Hamartoma, and nerve decompression was only performed (b). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Benign neoplasms of non-nerve sheaths origin or benign non-nerve sheath tumors (BNNST) of peripheral nerves Lipofibromatous hamartoma of the nerves Lipofibromatous Hamartoma of the Nerves (LHN) or neural fibrolipoma is an infrequent peripheral nerve tumor mostly involving the median nerve and its digital nerves [8]. It has been reported to be correlated with macrodactyly or macrodystrophia lipomatosa at birth [13,62,63]. LHN has a characteristic “cable-like” appearance on T1 and T2-weighted images [62–64]. Due to fact that the neoplasm is “imbedded” within the nerve fibers, it is difficult to be dissected in tumor free margins, therefor excision is rarely recommended [64]. Symptom based treatment management is suggested in terms of nerve decompression [65]. A case of LHN is presented in Fig. 2.
Benign triton tumor
Desmoid-Type fibromatosis
Benign Triton Tumor (BTT)s are neoplasms of neural and mature skeletal muscle cells with limited number published in the literature termed otherwise as hamartomata [13,59]. By predilection involving large peripheral nerves or plexi like sciatic nerve and brachial plexus most commonly in infancy or childhood [13,59]. Peripheral neuropathy symptoms when present lead the diagnostic approach. The principles of surgical resection apply here as well.
Desmoid-Type Fibromatosis (DTF) involving peripheral nerves is an aggressive neoplasia characterized by infiltrative but benign fibroblasts. These tumors due to the fibrous tissue behave as a firm mass. Cases of DTF involving peripheral nerves have been sporadically reported in the literature [66,67]. Desmoid Tumors are often symptomatic but there is no consensus in the literature for the optimal treatment; thus, each case should be discussed on a customized patient-specific way.
Nerve sheath ganglions – intraneural ganglions Hemangioblastoma Literature review revealed cases of nerve sheath ganglia (NSG) involving peripheral nerves [60,61]. Ganglia represent most likely a degenerative process than a true neoplasm. Nerve Sheath Ganglia are cystic formations in the epineurium of the nerves and they contain clear fluid of jelly-like consistency. NSG mostly involve the peroneal nerve while case of other peripheral nerve involvement have been reported [15,60,61]. The nerve gets the appearance of focal swelling that corresponds to the cystic formation. Symptoms derive from the compression effect generated by the cyst. Either described as acute or diffuse, radiating pain and deficit should be taken into consideration in the decision making process of the treatment management. Options include local resection while cyst decompression is an accepted alternative in the case that the nerve integrity is at risk [15,60,61].
Hemangioblastoma is a rare begin tumor with approximately 25% of them encountered in the Von Hippel – Lindau (VHL) syndrome [68]. Albeit the vast majority arises in the Central Nervous System, cases of peripheral sites have been reported [68–70]. Clinically, patients present with progressive neurological symptoms resulting from progressive deficit. Surgical resection with clear margins appears to be the treatment of choice [68]. Ganglion cyst – extraneural ganglion cysts Ganglion Cysts as it has aforementioned can be either intraneural or extraneural. Many theories have described the possible aetiology of the extraneural ones. Synovial hernias, trauma or
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Fig. 3. A 29-year-old male presented to the Outpatient’s Clinic complaining of pain his right knee arising at the level of the lateral head of the gastrocnemius. Following a thorough clinical examination, an MRI was obtained demonstrating a cystic fluid-like mass in close proximity to the common peroneal nerve yielding symptoms from nerve compression (a and b). The mass was not suspicious for any malignant component as it was homogeneous with no invasive behaviour to the surrounding tissue envelope. After having discussed the risks and benefits of the procedure, the patient was consented for resection through a direct approach over the area of interest in an extensile way (c). Intraoperative, the cystic formation was confirmed (d) and the decision was to evacuate the cyst, by decompression of the jelly-like component (e). The common peroneal nerve was intact. Pathology report was consistent with ganglion cyst. The postoperative period was uneventful and the patient is free of any clinical worrisome symptoms 18 months later.
mucoid degeneration are among the most commonly suggested [8,71]. Ganglia account for the 50–70% of the tumors of the hand [8] while the other frequent area is around the common peroneal nerve. Rawal et hypothesized that the proximal tibiofibular joint is the origin of the peroneal ganglia [72,73]. Symptoms originate secondary to the pressure effect on the nerve. If the symptoms can be tolerated by the patient, then observation and monitoring is a choice within the treatment arsenal as there have been reported cases in which ganglia spontaneously disappeared in about 40% of them [8,74,75]. Other than monitoring, aspiration or complete surgical resection of the cyst are the other options. It is an importance to keep in mind that the recurrence rate is relatively high [76]. A case of extraneural Ganglion Cyst is presented in Fig. 3. Traumatic neuromas Traumatic Neuromas (TN) are typical benign tumors that develop post neurotmesis resulting from the lack of endoneurium tube during nerve regeneration. Axonal regrowth, development and distribution seems to be the key role in the TN formation [77]. Dysesthesia and Traumatic Neuropathic Pain are among the most discomforting symptoms that have to be addressed while neuromas as a tumoral mass itself appears to be firm occasional painful nodule [78]. Several treatment modalities have been proposed with raging outcomes [77–79]. A diagnostic dilemma appears when the initial surgery was oncological mandated and a new tumoral formation is noted in the surgical field in proximity with the nerve during the follow up. This case scenario has been most of the
times in the agenda of Tumor Boards Summits raising the question of tumor recurrence over neuroma formation. Tumor-like lesions Neuritis ossificans or intraneural heterotopic ossification Limited literature is available for Intraneural Heterotopic Ossification (IHO). Woltman et al. in 1946 followed by Catalano et al. in several years later in 1992 were among the first to have reported a case of IHO or neuritis ossificans [80,81]. Not typically encountered lesion is characterized by apposition of fibrovascular tissue with an intermediate zone of osteoid and a periphery of ossification microscopically [82–84]. Trauma is proposed as a risk factor [82,83]. Symptoms of progressive muscular weakness, painful mononeuropathy, focal swelling alongside the course of involved nerve should be assessed in the clinical examination [82,84]. Biopsy should be considered when possibility of malignancy is suspected as specific types of osteoblastic sarcomas exist. Management of IHO is symptom oriented and many factors should be taken into consideration in the setting of prevention by possible iatrogenic nerve damage. Declaration of Competing Interest All authors report no conflict of interest in relation to this study.
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Please cite this article as: Z.T. Kokkalis, N.A. Stavropoulos and A.F. Mavrogenis et al., Benign peripheral nerve tumors, Injury, https: //doi.org/10.1016/j.injury.2019.10.054