ABSTRACT
Objective
To compare the clinical, electrophysiological, and nerve ultrasound characteristics of peripheral nervous system lymphoma (PNSL) and non‐systemic vasculitic neuropathy (NSVN).
Methods
Between July 2015 and May 2026, 9 PNSL patients and 7 NSVN patients were retrospectively enrolled. Clinical characteristics, electrophysiological studies, and nerve ultrasound data were collected. Cross‐sectional area (CSA) was measured at predetermined sites of peripheral nerves.
Results
The PNSL group showed significantly higher rates of cranial nerve involvement (66.7% vs. 0%, p = 0.011) and nerve root/plexus involvement (88.9% vs. 0%, p = 0.001) than the NSVN group. Although CSA at most median and ulnar nerve sites did not differ significantly between groups, the PNSL group showed significantly higher CSA of the cervical roots and brachial plexus than the NSVN group (C5, C6, upper trunk, middle trunk, and lower trunk; p = 0.001–0.018) except C7 root. In the PNSL group, the CSA was significantly greater on the initially affected side than on the contralateral side (p < 0.001), whereas in the NSVN group the CSA was significantly greater on the contralateral side than on the onset side (p = 0.005). The maximum‐CSA ratio between bilateral homonymous nerves (affected onset/contralateral) was significantly higher in PNSL than in NSVN (1.32 vs. 0.88, p < 0.001).
Conclusions
PNSL shows persistent severe focal enlargement favoring the initially‐affected side and frequent cranial/root involvement, whereas NSVN exhibits mild‐to‐moderate, variable enlargement with rare cranial/root involvement. Nerve ultrasound may serve as a noninvasive screening tool prior to PET/CT and biopsy.
Keywords: mononeuritis multiplex, neurolymphomatosis, peripheral nerves, ultrasonography, vasculitis
Nerve ultrasound distinguishes peripheral nervous system lymphoma (PNSL) from non‐systemic vasculitic neuropathy (NSVN). PNSL shows severe focal, persistent enlargement on the initially affected side with frequent cranial/root involvement; NSVN presents milder, variable, and contralateral‐predominant enlargement, especially in newly involved nerves. This technique offers noninvasive pre‐biopsy screening.
1. Introduction
Peripheral nervous system lymphoma (PNSL) is a rare form of neurolymphomatosis, defined as lymphomatous infiltration of the peripheral nervous system. Neurolymphomatosis comprises primary and secondary forms, involving either the central or peripheral nervous system [1, 2]. Overall, neurolymphomatosis occurs in < 1% of all non‐Hodgkin lymphomas (NHLs) [1], and diffuse large B‐cell lymphoma (DLBCL) is the predominant histological subtype [1, 2]. Primary PNSL is exceedingly rare, representing only approximately 0.1% of extranodal lymphomas [3]. The clinical manifestations of PNSL are diverse, presenting as mononeuropathy multiplex, multiple radiculopathy and cranial nerve involvement [1]. Non‐systemic vasculitic neuropathy (NSVN) refers to a localized vasculitis of the epineurial vessels supplying peripheral nerves, without systemic involvement [4, 5]. In contrast to PNSL, NSVN is more frequent, although its exact incidence remains unknown. Among vasculitic neuropathies, NSVN is the most common single entity, accounting for approximately 26%–28% of cases [6]. Both PNSL and NSVN present predominantly with asymmetric mononeuropathy multiplex, characterized by limb numbness, pain, and weakness. Electrophysiologically, both disorders manifest a sensorimotor axonal pattern and may show transient symptomatic improvement with corticosteroid therapy, rendering early clinical misdiagnosis highly likely [2, 7]. Yet PNSL requires combination chemotherapy for definitive disease control, whereas corticosteroid monotherapy offers only transient symptomatic relief. Consequently, diagnostic delay permits sustained tumor infiltration and progressive multi‐nerve involvement, markedly worsening prognosis. This clinical overlap precludes early differentiation based on clinical presentation and electrophysiological studies alone. Definitive diagnosis ultimately relies on histopathological evidence and whole‐body fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) evaluation [1, 8, 9], the former being invasive and time‐consuming and the latter expensive, radiation‐exposing, and of limited accessibility. Therefore, an early discriminative detection method needs to be explored to assist differential diagnosis and provide evidence for subsequent PET/CT or tissue biopsy.
High‐frequency nerve ultrasound is a noninvasive, convenient, and reproducible imaging modality that has been widely used in the evaluation of peripheral neuropathies. Ultrasound can quantitatively measure nerve cross‐sectional area (CSA), assess internal echotexture, fascicular architecture integrity, and blood flow signals, providing important morphological information for peripheral neuropathies. A previous case report described the “fried‐egg sign” as a characteristic ultrasound feature of neurolymphomatosis: on transverse scans, a central hyperechoic avascular core of relatively preserved nerve fibers is encircled by a hypoechoic, hypervascular peripheral zone of epineurial tumor infiltration [10]. In lymphoma, nerve ultrasound has been used to identify nerve enlargement [7, 10, 11, 12] and guide targeted biopsy [10, 11], facilitating diagnosis. In NSVN, Goedee et al. [13] reported proximal multifocal enlargement of upper limb nerves in a small sample (n = 5). However, existing evidence has been largely limited to case reports; systematic characterization of nerve ultrasound features in PNSL and NSVN is lacking, and direct comparisons between the two groups remain scarce.
This study aimed to systematically compare the nerve ultrasound features of PNSL and NSVN in conjunction with clinical, electrophysiological, and laboratory findings to delineate differences in nerve involvement patterns and enlargement distribution, and to evaluate the utility of high‐frequency ultrasound for early differential diagnosis.
2. Methods
2.1. Study Participants
Between July 2015 and May 2026, 9 patients with PNSL and 7 patients with NSVN were retrospectively enrolled at Peking Union Medical College Hospital. In the PNSL group, 8 patients were pathologically confirmed or had positive cerebrospinal fluid (CSF) cytology for lymphoma. One patient (L6, a 94‐year‐old woman; Table 1) declined tissue biopsy due to advanced age; however, PET/CT demonstrated multifocal FDG hypermetabolism in cranial nerves, spinal nerve roots, and nerve plexuses (maximum standardized uptake value [SUVmax] 7.2). She was refractory to treatment with corticosteroids and intravenous immunoglobulin (IVIg) therapy. Based on the clinical presentation of mononeuropathy multiplex, an axonal electrophysiological pattern, a rapidly fatal course within 2 months, and a negative workup for systemic vasculitis or other connective tissue diseases, a comprehensive clinical diagnosis of lymphoma was established. The NSVN group comprised 7 patients with clinically definite or probable non‐systemic vasculitic neuropathy, without evidence of systemic vasculitis or other connective tissue diseases. Patients with diabetes‐related, chemoradiotherapy‐related, or hematological disease‐related neuropathy (e.g., POEMS syndrome, monoclonal gammopathy of undetermined significance), hereditary peripheral neuropathy, chronic inflammatory demyelinating polyneuropathy, or other identifiable etiologies were excluded from both groups. All patients provided written informed consent, and the study was approved by the hospital ethics committee.
TABLE 1.
Clinical characteristics of patients with peripheral nervous system lymphoma (PNSL).
| ID | Age/gender | Duration (m) | Histopathological subtype | Primary neurolymphomatosis | PET‐CT | Diagnostic method | Affected sites | Mechanism | Treatment | Follow‐up duration (m) | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|
| L1 | 54/F | 5 | PNL (B‐cell) | Yes | Focal left foraminal root | CSF cytology | Root + multifocal mononeuropathy | Infiltrative + Inflammatory | Chemotherapy | 130 | Improved |
| L2 | 59/M | 8 | IVLBCL | No | Normal | Skin + muscle biopsy | Root + mononeuropathy | Infiltrative | Chemotherapy | 125 | Stable |
| L3 | 61/M | 20 | B‐cell lymphoma | No | Focal L5–S1 root, SUVmax 4.0 | Previously diagnosed; CSF cytology + PET‐CT | Root + multifocal mononeuropathy | Infiltrative | Chemotherapy | 4 | Stable |
| L4 | 48/M | 4 | DLBCL | No | — | Previously diagnosed + new biopsy | Multifocal mononeuropathy | Infiltrative + Inflammatory | Chemotherapy | 81 | Lost to follow‐up |
| L5 | 55/F | 24 | Aggressive B‐cell lymphoma | Yes | Focal left S1 root | Nerve root biopsy | Root + multifocal mononeuropathy | Infiltrative | Chemotherapy | 17 | Improved |
| L6 | 94/F | 7 | Lymphoma | Yes | Multiplex cranial and spinal plexus, SUVmax 7.2 | Clinical + PET‐CT + rapid fatal outcome | Multifocal mononeuropathy | Infiltrative | Corticosteroid + IVIG | 2 | Died |
| L7 | 46/M | 12 | DLBCL | No | Multilevel cervical, brachial, lumbosacral plexus | Nerve root biopsy | Root + multifocal mononeuropathy | Infiltrative | Chemotherapy | 98 | Improved |
| L8 a | 32/F | 1 | NKTCL | No | Spinal cord & roots; CN VIII root, SUVmax 12.8 | CSF cytology + biopsy | Root + multifocal mononeuropathy | Infiltrative | Chemotherapy | 2 | Stable |
| L9 | 38/M | 1 | PTCL | Yes | Normal | Lymph node biopsy | Root + multifocal mononeuropathy | Inflammatory | Chemotherapy | 4 | Improved |
Abbreviations: CSF, cerebrospinal fluid; DLBCL, diffuse large B‐cell lymphoma; IVIG, intravenous immunoglobulin; IVLBCL, intravascular large B‐cell lymphoma; NKTCL, Natural Killer/T‐cell lymphoma; PNL, primary neurolymphomatosis; PTCL, peripheral T‐cell lymphoma; SUVmax, maximum standardized uptake value.
One patient (L8) presented with simultaneous onset in the left upper and right lower limbs and was counted in both the upper‐limb and lower‐limb onset subgroups.
2.2. Clinical and Electrophysiological Assessment
Clinical data were collected, including age, sex, disease duration (months), affected limb at onset, symptoms, cranial nerve/spinal nerve root/plexus involvement, treatment regimen, and follow‐up outcomes. Blood tests included anti‐neutrophil cytoplasmic antibody (ANCA), anti‐nuclear antibody (ANA) profiles, erythrocyte sedimentation rate (ESR), vitamin B12, folate, anti‐ganglioside antibodies, and paraneoplastic antibodies (anti Hu, Yo, and Ri). CSF cytology, protein, and flow cytometry were collected in some patients. Electrophysiological studies were performed using a Nicolet EMG machine (CareFusion, Middleton, Wisconsin) for electromyography (EMG) and nerve conduction studies (NCSs). Room temperature was maintained to keep skin temperature above 31°C. Nerve conduction included motor nerve conduction studies (MNCS) and sensory nerve conduction studies (SNCS) of the median, ulnar, peroneal, and tibial nerves (one patient underwent only lower limb studies, and one only upper limb studies); all patients underwent bilateral nerve studies. Axonal versus demyelinating features were classified, and needle EMG was performed in all patients as clinically indicated, with the number of examined muscles varying among patients according to clinical needs. Electrophysiological nerve root involvement was defined as denervation and/or reinnervation in at least 2 muscles of the same myotome innervated by different peripheral nerves, with or without paraspinal muscle involvement; involvement of 2 or more root levels was classified as multiple radiculopathies. Overall, the median (IQR) number of muscles examined per patient was 9 (9–10) in the PNSL group and 2 (2–4.5) in the NSVN group. The final determination of nerve root involvement was made by integrating clinical, electrophysiological, and imaging findings. Some patients had undergone contrast‐enhanced MRI of the brachial plexus, cervical nerve roots, and lumbosacral plexus, as well as whole‐body PET/CT. Tissue biopsies (nerve, skin, lymph node and other sites) were obtained in some patients.
2.3. High‐Frequency Nerve Ultrasound Protocol
An 8–12 MHz high‐frequency linear array probe (LOGIQ e; General Electric Company, Wuxi, China) was used for nerve ultrasound examination. For bilateral median, ulnar, and brachial plexus nerve examinations, patients were placed in the supine position with the upper limbs naturally extended; the probe was placed perpendicular to the nerve course to obtain the image with the smallest cross‐sectional area. For bilateral tibial, common peroneal, and sciatic nerve examinations, patients were placed in the prone position with the lower limbs naturally extended, and the same method was used to obtain CSA. CSA was measured using the trace method, tracing along the inner edge of the hyperechoic nerve outer margin. The median nerve (at 10 anatomical sites, M1–M10), ulnar nerve (at 10 anatomical sites, U1–U10), cervical nerve roots (C5–7), brachial plexus trunks (upper, middle, and lower trunks), tibial and common peroneal nerves were examined bilaterally as previously described [14, 15]. The exact anatomical definitions of all measurement sites are provided in the Supporting Information.
The upper limit of normal (ULN) was defined as mean + 2 standard deviations of nerve CSA in healthy controls (HC). Enlargement was graded as mild‐to‐moderate (> 1 × ULN but < 2 × ULN) or severe (≥ 2 × ULN) [14, 15]. Patients presented with mononeuropathy multiplex with varying affected nerves. To eliminate the influence of individual and site‐specific differences in normal values, standardized CSA was calculated: standardized CSA = patient CSA/mean CSA of HC at the same site. HC reference CSA values were derived from our previous study [14]. For patients with multi‐limb onset, the onset side was defined separately for each affected limb.
2.4. Statistical Analysis
Statistical analyses were performed using SPSS version 30.0 (IBM Corp., Armonk, NY, USA). The Shapiro–Wilk test showed that continuous data were not normally distributed; data are expressed as median (interquartile range [IQR]), and intergroup comparisons were performed using the Mann–Whitney U test. Intragroup paired comparisons were performed using the Wilcoxon signed‐rank test. Categorical data are described as count (percentage) and were compared using the two‐sided Fisher exact test. p < 0.05 was considered statistically significant.
3. Results
3.1. Comparison of Clinical Characteristics Between PNSL and NSVN
Table 2 compares the clinical characteristics of the two groups (Tables 1 and 3). The PNSL group comprised 9 patients (median age 54 years; 6 males), and the NSVN group comprised 7 patients (median age 41 years; all males). Median disease duration was 7 (1–24) months in the PNSL group and 8 (1–204) months in the NSVN group. Both groups predominantly presented with single‐limb onset (77.8% vs. 100%) and mononeuropathy multiplex (88.9% vs. 100%). Of the 2 patients with PNSL who had multi‐limb onset, 1 had simultaneous onset in the left upper and right lower limbs. Consequently, the 9 PNSL patients accounted for 10 onset limbs (5 upper, 5 lower). Cranial nerve involvement (66.7% vs. 0%, p = 0.011) and nerve root/plexus involvement (88.9% vs. 0%, p = 0.001) were significantly more common in the PNSL group than in the NSVN group. Of note, one PNSL patient (L8) without clinical or electrophysiological evidence of root involvement was classified as having root/plexus involvement based on FDG hypermetabolism of the spinal nerve roots on PET/CT.
TABLE 2.
Comparison of clinical, electrophysiological, and outcome features between PNSL and NSVN.
| Characteristic | PNSL (n = 9) | NSVN (n = 7) |
|---|---|---|
| Demographics | ||
| Median age (year) | 54 | 41 |
| Male sex, n (%) | 6 (66.7%) | 7 (100%) |
| Disease duration, median (range) (m) | 7 (1–24) | 8 (1–204) |
| Clinical presentation | ||
| Single‐limb onset, n (%) | 7 (77.8%) | 7 (100%) |
| Multifocal mononeuropathy, n (%) | 8 (88.9%) | 7 (100%) |
| Cranial nerve involvement, n (%) | 6 (66.7%) | 0 (0%) |
| Spinal root/plexus involvement, n (%) | 7 (77.8%) | 0 (0%) |
| Pathological mechanism | ||
| Infiltrative, n (%) | 8 (88.9%) | 0 (0%) |
| Inflammatory, n (%) | 3 (33.3%) | 7 (100%) |
| Diagnostic findings | ||
| Abnormal CSF cytology, n/N (%) | 3/6 (50%) | — |
| MRI positive for nerve root/plexus, n/N (%) | 2/3 (66.7%) | — |
| PET‐CT positive for nerve, n/N (%) | 5/8 (62.5%) | — |
| Nerve or nerve root biopsy positive, n/N (%) | 2/3 (66.7%) | 3/3 (100%) |
| Electrophysiology | ||
| Axonal pattern, n (%) | 9 (100%) | 7 (100%) |
| Isolated radiculopathy | 0 | 0 |
| Multiradicular pattern | 7 (77.8%) | 0 |
| Axonal multifocal mononeuropathy | 7 (77.8%) | 7 (100%) |
TABLE 3.
Clinical and Electrophysiological Characteristics of Patients with non‐systemic vasculitic neuropathy (NSVN).
| ID | Age/gender | Duration (m) | Multifocal mononeuropathy | Treatment | Treatment response |
|---|---|---|---|---|---|
| V1 | 41/M | 1 | Yes | Prednisone | Responsive |
| V2 | 44/M | 8 | Yes | Prednisone | Responsive |
| V3 | 46/M | 18 | Yes | Prednisone | Non‐responsive |
| V4 | 29/M | 204 | Yes | Prednisone | Responsive |
| V5 | 40/M | 8 | Yes | IVIG | Non‐responsive |
| V6 | 43/M | 10 | Yes | Prednisone | Responsive |
| V7 | 32/M | 1 | Yes | Prednisone | Responsive |
Abbreviation: IVIg, intravenous immunoglobulin.
3.2. Comparison of Electrophysiological Characteristics Between PNSL and NSVN
All patients in both groups (100%) showed axonal mononeuropathy multiplex. Electrophysiologically, 77.8% (7/9) of patients in the PNSL group showed concomitant nerve root involvement, all with a multiple radiculopathy distribution, whereas no NSVN patient showed electrophysiological evidence of nerve root damage (p = 0.003). Neither group showed obvious demyelination or conduction block.
3.3. Nerve Ultrasound Characteristics of PNSL and NSVN
3.3.1. Comparison of CSA at Each Site of the Median, Ulnar, and Brachial Plexus Between PNSL and NSVN
Figure 1 shows the between‐group comparison of CSA across 10 sites of the median and ulnar nerves. Significant differences were limited to the U2 site (p = 0.04), with higher values in PNSL; all other sites showed no significant differences (Figure 1A,B, Tables S1.1 and S1.2). Intergroup comparison of CSA of the brachial plexus and cervical nerve roots showed that the median CSA in the PNSL group was significantly higher than that in the NSVN group at 5 sites (C5: 6.92 vs. 5.13 mm2, p = 0.001; C6: 10.45 vs. 7.93 mm2, p = 0.002; upper trunk: 21.50 vs. 15.75 mm2, p = 0.002; middle trunk: 13.55 vs. 11.35 mm2, p = 0.018; lower trunk: 16.05 vs. 11.10 mm2, p = 0.010), with only C7 failing to reach significance (p = 0.068) (Figure 1C, Table S1.3).
FIGURE 1.
Cross‐sectional area (CSA) at each site of the median nerve, ulnar nerve, and brachial plexus in peripheral nervous system lymphoma (PNSL) and non‐systemic vasculitic neuropathy (NSVN). Data are presented as median (IQR). (A) Median nerve at 10 sites (M1–M10). (B) Ulnar nerve at 10 sites (U1–U10). (C) Brachial plexus at 6 sites (C5, C6, C7, upper trunk, middle trunk, lower trunk). Intergroup comparisons were performed using the Mann–Whitney U test. CSA, cross‐sectional area; IQR, interquartile range.
3.3.2. Intergroup and Intragroup Paired Comparisons of Standardized CSA in PNSL and NSVN
Because the affected nerves differed among patients, CSA was normalized to the site‐matched mean of healthy controls (standardized CSA; Table 4). On the onset side, the standardized CSA was significantly higher in the PNSL group than in the NSVN group (2.86 [2.39–3.47] vs. 1.26 [0.93–1.35]; p < 0.001), approximately three times the site‐matched normal reference mean. In contrast, on the contralateral side, the standardized CSA was higher in the NSVN group than in the PNSL group (1.56 [1.24–1.95] vs. 1.10 [1.03–1.38]; p = 0.029). Within‐group comparisons corroborated this asymmetry: in the PNSL group, the onset‐side standardized CSA was significantly greater than the contralateral value (p < 0.001), whereas in the NSVN group the contralateral standardized CSA was significantly greater than the onset‐side value (p = 0.005).
TABLE 4.
Intergroup and intra‐group comparison of standardized CSA between PNSL and NSVN patients.
| Variables | PNSL (n = 11) | NSVN (n = 14) | Intergroup p | Intergroup r |
|---|---|---|---|---|
| Onset standardized CSA | 2.86 (2.39, 3.47) | 1.26 (0.93, 1.35) | < 0.001 | 0.86 |
| Contralateral standardized CSA | 1.10 (1.03, 1.38) | 1.56 (1.24, 1.95) | 0.029 | −0.52 |
| Intra‐group p | < 0.001 | 0.005 | ||
| Intra‐group r | 1.00 | −0.81 |
Note: Standardized CSA = patient CSA/site‐matched reference CSA of healthy controls. Data are presented as median (IQR). Intergroup comparisons were performed using the Mann–Whitney U test. Intra‐group paired comparisons between onset and contralateral nerve were performed using the paired Wilcoxon signed‐rank test. p < 0.05 indicates statistical significance. The onset‐side standardized CSA was significantly greater in PNSL group than in the NSVN group (p ＜0.001), whereas the contralateral standardized CSA was siginificantly greater in the NSVN group than in the PNSL group (p = 0.029). Within groups, the onset‐side value exceeded the contralateral value in PNSL (p＜0.001), whereas the opposite pattern was observed in NSVN (p = 0.005). Bold values indicate statistically significant intergroup and intragroup p values.
3.3.3. Analysis of Maximum CSA of Peripheral Nerves in PNSL and NSVN
Analyses based on the maximum CSA of each affected nerve (the thickest point along the nerve) yielded consistent results. In the PNSL group, the maximum CSA on the onset side was higher than that on the contralateral side for all nerves examined, whereas in the NSVN group it was lower than or close to the contralateral value (Figure 2, Table S2). The onset‐to‐contralateral ratio of maximum CSA, a direct measure of enlargement asymmetry, was significantly higher in the PNSL group than in the NSVN group (1.32 [1.11–1.96] vs. 0.88 [0.69–0.97]; p < 0.001, r = 0.92; Figure 3). The ratio exceeded 1 in all PNSL patients, whereas most NSVN patients had ratios below or close to 1.
FIGURE 2.
Maximum CSA of individual nerves on the onset side and the contralateral side in PNSL and NSVN patients. Each dot represents the maximum CSA of one nerve in an individual patient. Horizontal lines indicate the median. (A) Median nerve. (B) Ulnar nerve. (C) Tibial nerve (measured at the popliteal fossa). (D) Common peroneal nerve. CSA, cross‐sectional area.
FIGURE 3.
Intra‐individual comparison of maximum nerve CSA ratio (onset/contralateral) in patients with PNSL and NSVN. Each dot represents one nerve. The horizontal lines indicate the median. The dashed line represents a ratio of 1 (onset = contralateral). PNSL patients showed a significantly higher ratio than NSVN patients (median 1.32 vs. 0.88; Mann–Whitney U test, p < 0.001, r = 0.92).
3.3.4. Ultrasonographic Morphological Characteristics of PNSL and NSVN
PNSL nerves displayed persistent marked enlargement, predominantly on the side of onset, whereas NSVN nerves were normal or only mildly to moderately enlarged, with the degree of enlargement paralleling recent disease activity in the corresponding limb. Representative images are shown in Figure 4. In PNSL patients L9 and L4, the median nerve was enlarged on the onset side (moderately to markedly in L9 and markedly in L4), with normal CSA (L9) or mildly enlargement (L4) on the contralateral side (Figure 4A,B,E,F). In NSVN Patient V1, the median nerve at site M8 was at the upper limit of normal on the onset side but mildly to moderately enlarged on the contralateral side, where new symptoms had developed during the preceding month (Figure 4C,G); this enlargement was less pronounced than in PNSL. In NSVN Patient V2, with bilateral symptoms for 8 months without recent progression, the median nerve at M8 was at the upper limit of normal bilaterally (Figure 4D,H).
FIGURE 4.
Representative high‐resolution ultrasound images of nerve morphology in PNSL and NSVN patients. PNSL1: PNSL Patient 9—(A, E) Moderately‐to‐markedly enlarged median nerve at site M9 on the onset side (A) with normal CSA on the contralateral side (E). PNSL2: PNSL Patient 4—(B, F) Markedly enlarged median nerve at site M8 on the onset side (B) with mildly enlarged CSA on the contralateral side (F). NSVN1: NSVN Patient 1—(C, G) Initial onset side (C) showing median nerve at site M8 at the upper limit of normal; recent symptomatic side (G) showing mild‐to‐moderately enlarged median nerve at site M8, less pronounced than in PNSL. NSVN2: NSVN Patient 2—(D, H) Bilateral median nerves at site M8 at the upper limit of normal.
Two PNSL patients underwent follow‐up nerve ultrasound after chemotherapy. Both patients showed symptomatic improvement with reduced CSA of the previously enlarged nerve (approximately 50% in L1 after 5 cycles; mild reduction in L9 after 2 cycles).
3.4. PET/CT, CSF, and Biopsy Findings
In the PNSL group, whole‐body PET/CT revealed FDG hypermetabolism along peripheral nerves or nerve roots in 62.5% (5/8) of patients, and CSF cytology identified atypical cells in 50% (3/6). Three patients underwent nerve or nerve root biopsy, which confirmed lymphoma in 2 (Table 1).
4. Discussion
In this study, we compared the neuromorphological features of PNSL and NSVN using high‐frequency nerve ultrasound and found that, despite substantial overlap in clinical and electrophysiological phenotypes, the ultrasound characteristics differed markedly. PNSL was characterized by multi‐site marked enlargement of the brachial plexus, focal marked enlargement of peripheral nerves on the affected side, marked bilateral asymmetry, and frequent concomitant cranial nerve and nerve root involvement. In contrast, NSVN was characterized by a normal brachial plexus in our cohort, mild‐to‐moderate enlargement of recently affected nerves and rare involvement of cranial nerves and nerve roots. High‐frequency nerve ultrasound therefore provides distinctive clues for the early differentiation of PNSL from NSVN and may serve as a complementary tool to electrophysiology and nerve root MRI, guiding subsequent targeted examinations such as PET/CT and biopsy.
PNSL ultrasound is characterized by focal marked nerve enlargement on the affected side, fascicular structural changes, and increased vascularity. Lee et al. [10] described the “fried‐egg sign”—a central hyperechoic, avascular core of residual fascicles surrounded by a hypoechoic, hypervascular rim of epineurial tumor infiltration on transverse scans—as a relatively specific ultrasound feature of neurolymphomatosis. All 5 PNSL patients with upper‐limb onset showed focal marked enlargement of the affected nerves; 5 patients with lower‐limb onset also had thicker onset‐side nerves, although the asymmetry was less pronounced. The patient whose findings most closely resembled the fried‐egg sign (L6) had a median nerve CSA of 93 mm2 with complete loss of fascicular architecture corresponding segmental FDG uptake on PET/CT, and a rapid fatal course (Figure S1), suggesting extensive endoneurial tumor infiltration. In a systematic review, nerve ultrasound demonstrated enlargement and hypervascularization in 88.2% (15/17) of examined patients with neurolymphomatosis [1]. Ultrasound phenotypes may also vary across lymphoma subtypes. B‐cell lymphoma accounts for 73%–90% of neurolymphomatosis, with DLBCL predominant (68%–78%) [1, 2]. Overall, 75% (6/8) of our histologically confirmed cases were B‐cell lymphomas. Consistent with the case reported by Shi et al. [16], one NK/T‐cell lymphoma patient had no evident nerve enlargement, whereas skin biopsy from their case revealed vascular infiltration of tumor cells. Focal marked nerve enlargement with rich vascularity and a hypoechoic, mass‐like change should therefore raise strong suspicion of lymphoma.
In contrast, NSVN nerves showed only mild‐to‐moderate enlargement, which predominated on the recently affected side. Goedee et al. [13] examined 16 patients with vasculitic neuropathy (including 5 with NSVN) and found mild‐to‐moderate multifocal enlargement of upper‐limb nerves proximal to entrapment sites (sensitivity 94%, specificity 88%). NSVN patients in our cohort showed a similar pattern. Moreover, in some of our NSVN patients, the CSA of earlier‐affected nerves was even normal or slightly reduced. This divergence in enlargement patterns reflects fundamentally different pathological mechanisms. NSVN is an immune‐mediated vasculitis with lesions in the vasa nervorum of the epineurium, featuring inflammatory cell infiltration and luminal occlusion leading to axonal ischemic damage; the inflammation is self‐limited and reversible, and nerve edema can change with treatment or over the natural course of the disease. In contrast, most PNSL cases reflect direct tumor infiltration without self‐limitation, showing progressive enlargement.
Nervous system involvement was more extensive in PNSL than in NSVN. In our cohort, the frequencies of cranial nerve involvement (66.7% vs. 0%) and spinal nerve root or plexus involvement (88.9% vs. 0%) were both significantly higher in the PNSL group. In a systematic review of 459 patients with neurolymphomatosis, the infiltrated structures included peripheral nerves (56%), nerve roots (52%), nerve plexuses (33%), and cranial nerves (32%), with lumbosacral infiltration (40.6%) slightly more frequent than cervical infiltration (34.1%) [1]. Case reports have described involvement of the optic nerve [17], oculomotor nerve [18], trigeminal nerve [19, 20], facial nerve [21], and glossopharyngeal and vagus nerves [20]; isolated cranial neuropathy may even be the initial manifestation [18]. In our cohort, cranial nerve involvement was identified in 66.7% (6/9) of PNSL patients: 4 patients had clinical cranial neuropathy, and 2 additional patients showed cranial nerve hypermetabolism on PET/CT. Cranial nerve involvement is rare in NSVN (0%–9%) [4, 9, 22], and none of our NSVN patients had such involvement, consistent with previous reports. In NSVN presenting as mononeuropathy multiplex, brachial plexus enlargement is typically absent; notably, none of the 5 NSVN patients described by Goedee et al. [13] had brachial plexus enlargement. It is speculated that NSVN lesions are confined to epineurial arterioles and the self‐limited inflammation does not spread proximally, whereas PNSL is highly neurotropic and disseminates along the meninges and nerve roots. Accordingly, when mononeuropathy multiplex is accompanied by cranial nerve, nerve root, or plexus involvement, PNSL should be strongly suspected, and whole‐body PET/CT and nerve biopsy should be pursued promptly.
Nerve ultrasound can also be used to monitor treatment response dynamically. In our cohort, two PNSL patients showed CSA reduction after chemotherapy, accompanied by symptomatic improvement. Previous reports support this observation. Soleimani et al. [12] described a patient with DLBCL in whom nerve CSA increased progressively with tumor recurrence and decreased after treatment, and Wada et al. [7] reported a “dramatic” post‐chemotherapy reduction of median nerve and brachial plexus enlargement (from 54 to 16 mm2 and from 167 to 63 mm2, respectively). Notably, although we did not perform systematic dynamic follow‐up of NSVN patients, intra‐individual differences related to time since onset—normalization or slight reduction of CSA in earlier‐affected nerves versus enlargement of recently affected nerves—indirectly suggest that NSVN‐related nerve enlargement is dynamically reversible, in contrast to the persistent enlargement of untreated PNSL. Finally, ultrasound can precisely localize biopsy targets. For mass‐like nerve enlargement with corresponding PET/CT hypermetabolism, ultrasound‐guided biopsy may improve the diagnostic yield [10, 11].
PET/CT is valuable for diagnosing lymphoma and monitoring disease dynamics. In our cohort, the PET/CT positivity rate in the PNSL group was 62.5%. Higher positivity rates have been reported in neurolymphomatosis: 93.4% (284/304) in the systematic review by Kaulen et al. [1], and a sensitivity of 84%–100%. Nevertheless, PET/CT is expensive, involves radiation exposure, and is not universally accessible, whereas ultrasound is radiation‐free and easily repeatable. We therefore propose ultrasound for initial screening and dynamic monitoring, reserving PET/CT for comprehensive assessment of disease extent and biopsy planning.
This study has several limitations. First, this was a single‐center retrospective study with a small sample size, which precluded subgroup analyses. The two groups were not matched for age or sex, and selection and referral bias cannot be excluded, so the findings require validation in larger, prospectively enrolled cohorts. Second, owing to the retrospective design, ultrasound and electrophysiological examinations were performed at variable time points relative to disease onset and treatment, and the sonographers could not be blinded to the clinical diagnosis. Third, nerve ultrasound is operator‐dependent, and its ability to visualize deep structures, particularly the lumbosacral roots and plexus, is limited; in this regard, nerve ultrasound and contrast‐enhanced nerve root MRI are complementary. Fourth, needle EMG sampling was clinically guided rather than protocol‐based, so subclinical root involvement may have been underestimated. Future multicenter prospective studies with standardized, blinded ultrasound and electrophysiological protocols are warranted.
5. Conclusion
Peripheral nervous system lymphoma and non‐systemic vasculitic neuropathy show substantial clinical and electrophysiological overlap and similar short‐term responses to corticosteroids, yet their nerve ultrasound features differ markedly. PNSL is characterized by focal, marked nerve enlargement that predominates on the onset side, persists and progresses without treatment, and is frequently accompanied by nerve root and cranial nerve involvement. In contrast, NSVN shows mild‐to‐moderate nerve enlargement, predominantly affecting recently involved nerves, may regress over the disease course, and rarely involves nerve roots or cranial nerves in the mononeuropathy multiplex phenotype. High‐frequency nerve ultrasound can therefore aid in differentiating these two disorders, serving as a noninvasive complementary tool to electrophysiology and nerve root MRI before PET/CT and nerve biopsy, and allowing dynamic follow‐up to assess treatment response.
Author Contributions
Huihong Tian: conceptualization, investigation, data curation, software, methodology, writing – original draft. Nan Hu: data curation, conceptualization. Jianfeng Ding: data curation. Min Qian: data curation. Yiying Wang: data curation. Liying Cui: conceptualization. Jingwen Niu: conceptualization, supervision, project administration, writing – review and editing, validation. Mingsheng Liu: funding acquisition, conceptualization, validation, writing – review and editing, project administration, supervision.
Funding
National High Level Hospital Clinical Research Funding (2026‐PUMCH‐C‐008); National Key R&D Program of China (2022ZD0118003); China International Medical Foundation (Z‐2016‐20‐2402).
Ethics Statement
The study was approved by the Ethics Committee of the Peking Union Medical College Hospital (PUMCH) (JS1210). All enrolled patients in our database provided written, informed consent to be included in the study.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1:1. Comparison of median nerve ultrasound cross‐sectional areas between PNSL and NSVN.
Table S1:2 Comparison of ulnar nerve ultrasound cross‐sectional areas between PNSL and NSVN.
Table S1:3 Comparison of cervical roots and brachial plexus ultrasound CSA between PNSL and NSVN.
Table S2: Intra‐individual maximum CSA ratio (onset/contralateral) for all nerves.
Figure S1: Focal marked enlargement of the distal median nerve with increased intraneural vascularization in a clinically diagnosed lymphoma patient (L6).
Acknowledgements
Authors would like to thank all the authors of the original articles.
Contributor Information
Jingwen Niu, Email: vera_new@aliyun.com.
Mingsheng Liu, Email: liumingsheng_pumch@163.com.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1:1. Comparison of median nerve ultrasound cross‐sectional areas between PNSL and NSVN.
Table S1:2 Comparison of ulnar nerve ultrasound cross‐sectional areas between PNSL and NSVN.
Table S1:3 Comparison of cervical roots and brachial plexus ultrasound CSA between PNSL and NSVN.
Table S2: Intra‐individual maximum CSA ratio (onset/contralateral) for all nerves.
Figure S1: Focal marked enlargement of the distal median nerve with increased intraneural vascularization in a clinically diagnosed lymphoma patient (L6).
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.