3.1 Schwannomatosis is a benign tumor that is characterized by multiple peripheral schwannomas with central nervous-system (CNS) tumors and various defects of the nervous system. About 30%–40% of patients carry LZTR1 mutations. The tumorigenesis of schwannomatosis is a response to a somatic five-hit/three-step mechanism, resulting in the loss of function of genes adjacent to LZTR1 and the contiguous genes of locus 22q11.2q12.2. Paganini et al. immunostained for LZTR1 protein in 22 masses from nine unrelated patients. It is suggested that LZTR1 molecular analysis might help elucidate the molecular characteristics of schwannomatosis patients. Ding et al. suggest that the structural and functional abnormalities of the SMARCB1 gene might be the molecular basis of familial schwannomatosis. If the focus involves peripheral-nerve tissue, it can be accompanied by pain. Jordan et al., using a simple 10-point pain scale (SF-36) to explore the relationship between pain and mutation of the SMARCB1 and LZTR1 genes in schwannomatosis, found that the median pain score of the LZTR1 group was 3.9 and that of the SMARCB1 group was 0.5 (P = 0.0414). Not only was the pain of LZTR1 mutation patients significantly higher than that of SMARCB1 mutation patients, but their pain-related quality of life as assessed by SF-36 was significantly worse (P = 0.0106). Pain score was correlated with tumor volume (rho = 0.32471, P = 0.0499) but not with number of tumors (rho = 0.23065, P = 0.1696). Nervous-system defects include hypoacusis, tinnitus and amyotrophy. When the CNS tumor exerts pressure on the surrounding tissues, symptoms of sensory and motor disorders can appear. The course of disease is chronic and benign. Histopathological features are as follows: the tumor tissue has an intact capsule; the tumor body is a single, spindle-shaped Schwann cell; and the tumor cell mass is separated by the stroma and has thick blood vessels around it. In clinical practice, doctors should consider a diagnosis of schwannomatosis in patients with multiple schwannomas and perform an active physical examination and imaging examination of the nervous system. It is worth noting that Mehta et al. believe that schwannomatosis patients without LZTR1 mutation can have unilateral vestibular schwannoma. Asai et al. also reported a case of pathologically confirmed left-cerebellopontine vagal-schwannoma tumor in whose family members a diagnosis of NF1 or NF2 was ruled out; genetic analysis revealed a germline mutation of SMARCB1. Smith et al. also believe that patients with schwannomatosis may have vestibular schwannoma, which should not be considered an exclusion criterion for clinical diagnosis. However, Baruah et al. suggest that schwannomatosis should be excluded if MRI shows any vestibular schwannoma. Radek et al. also believe that the clinical features of schwannomatosis are similar to NF2 but that there are no vestibular schwannomas in schwannomatosis. The previous diagnostic standard ruled out schwannomatosis if there were a history of the bilateral vestibular neuroma, but whether unilateral vestibular neuroma can exclude schwannomatosis is worth further exploration.
One of the main obstacles in the study of schwannomatosis is the lack of robust tumor cell lines. At present, there is no suitable tool for studying the mechanism of and conducting drug discovery for schwannomatosis. The current standard treatment is still surgical resection.
3.2Imaging features of schwannomatosis
3.2.1 Ultrasonic characteristics
In this study, US examination often showed masses distributed along the nerve. Most were oval (21/36) or round (12/36) low-echo masses with enhanced shadows in the posterior of the mass. Fused tumors could be distributed in a beadlike fashion. Because of the different pathological components of masses, the internal echo could be homogeneous (9/36) or inhomogeneous (27/36). Borders were mostly clear, and shapes were regular. CDFI showed mainly point and strip blood flow signals, with Adler grade II (15/36) the most common. The opposite ends of each mass were connected by nerve fibers, and a tail sign (20/36) was found in some masses.
Masses were located in the muscle space; there was a slightly low-density, oval-shaped block shadow running longitudinally; and density could be equal or unequal. Enhancement scanning varied according to the pathological components of the tumor. In type II tumors, CT enhancement masses were almost uniformly enhanced; there was a mild enhancement in four cases, moderate and severe enhancement in 1 case each. The CT enhancement of type I, III and IV tumors was mainly unequal. Type I showed mainly central enhancement. Type III showed mainly peripheral light-to-moderate enhancement, and two of these five masses had no enhancement due to the cystic area in the center. All of the type IV tumors showed inhomogeneous enhancement, and their CT values increased by 20–45 HU.
The main MRI manifestations of masses in schwannomatosis were low and equal signal on T1W1, medium and high signal on T2W1 and mixed high signal on diffusion-weighted imaging (DWI). Edge and internal continuous enhancement can be seen on the enhanced scan, and the boundary between benign tumors and surrounding tissue is relatively clear. The results of this study were similar to those described in the extant literature. MRI is the most effective imaging diagnostic method for intraspinal tumors, as it can clearly distinguish various tissues and structures in the spinal canal and it has certain use for determining the origin, shape, size, quantity and adjacent structures of tumors. It can also be used to guide the formulation of the surgical plan. The whole spine must be scanned via MRI before intraspinal-tumor surgery; doctors must carefully observe the small foci to avoid a missed diagnosis.
3.2.4Advantages and disadvantages of different imaging modalities
Because US examination is inexpensive, very safe, convenient, easy to operate and without risk of radiation damage, it has become the first choice for screening and postoperative reexamination of schwannomatosis. However, because of the bone block, US examination is limited in the detection of intracranial and intraspinal lesions. CT has high spatial resolution and no overlapping of tissue structure images, allowing it to accurately judge the relationship between masses and surrounding tissues, which provides an important basis for clinical surgery; however, its soft-tissue resolution is poor. MRI has the advantages of high soft-tissue resolution and multi-directional imaging, which can better show the source of the tumor, as well as the relationship between masses and blood vessels/surrounding tissues; it is more conducive to differentiating between benign and malignant tumors, so it has become a prerequisite examination before surgery. Godel et al. compared the volumes of dorsal-root ganglia in 16 patients with schwannomatosis, 14 patients with NF2 and 26 healthy controls by MR neurography. Their study found that dorsal-root ganglion volume was the same in NF2 as in healthy controls, but not in schwannomatosis. Dorsal-root ganglia might be vulnerable sites in terms of origination of areflexia and sensory loss, as well as useful diagnostic markers in NF2. MRI examination is costlier than ultrasound and CT, and it is not suitable for patients who have non-demagnetized metal implants or claustrophobia. In addition, in recent years, some researchers have used positron emission tomography (PET) for imaging diagnosis of schwannomatosis, but PET imaging might not be a reliable predictor of malignant transformation in schwannoma, which reduces the enthusiasm for tumor surgery without obvious clinical symptoms or signs. This imaging modality is also expensive and difficult to promote.
3.2.5 Pathological features of schwannomatosis
In general, specimens have a capsule, and there are no nerve fibers in the tumor body. In terms of path morphology, two types of schwannoma tissue can be seen under the microscope. In type A tissue, tumor cells are arranged in bundles; cells within the tissue are spindle-shaped and arranged parallel to each other into palisades; the nucleus is thin and long; and there are abundant slender reticular fibers between the cells. Type B has few cells in the tissue. The arrangement of tumor cells is disordered and loose, with liquid between cells and fibers that can collect in the capsule. There is a large extracellular space between tissues, and abundant capillaries and blood sinuses between cells. Tumor blood vessels often show sinusoidal, spongy, or capillary-like dilation and hyaline change of blood vessel walls. In terms of immunophenotype, schwannomatosis is the same as classic soft-tissue schwannoma. Our 12 cases all showed diffuse positive S-100 protein expression, which could be used as the first marker. NF was generally not expressed, Ki-67 was below 3%, and patients were mostly positive for CD34 and vimentin.
3.2.6 Relationship between imaging manifestations and pathology
This study showed a certain correlation between tumor imaging and pathological properties in schwannomatosis. Because of the density of the cells in Antoni type A tissue, CT plain scan and US findings in lesions mainly composed of this tissue showed mostly moderate and slightly low density or echo. The uniformity of the internal density or echo depended on the amount of Antoni type B tissue. The distribution of Antoni type B tissue in the tumor was consistent with that of the low-density and low-echo areas. Antoni B areas easily become cystic, and their imaging features are round low-density areas with smooth inner walls. The enhancement range of the tumor varied greatly, from light to significant; the enhancement could be irregular or more uniform, or there could be interstitial or cystic low density in the enhancement area. This change was consistent with the distribution of multicystic space and hemorrhagic degeneration in Antoni type B tissue, similar to the characteristic manifestation of schwannoma on T2WI: target sign. In this study, 25 masses had enhancement amplitudes >20 HU, 5 of which were schwannomas with active growth. There were abundant blood sinuses in the tumors. The blood-rich Antoni type A tissues were enhanced, while enhancement of Antoni type B tissues was not obvious. In this study, 11 masses with enhancement <20 HU were found to have a large number of collagen fibers. Other causes of tumor enhancement included hyaline degeneration, hemorrhage and necrosis. CDFI revealed no significant blood flow signal in most lesions, only a small amount of linear color blood flow signal. The reason was that the wall of the tumor vessel was fibrosis and accompanied by thrombosis.
3.3 Differential diagnosis
Neurofibromatosis type 2（NF2）
NF2 is an autosomal-dominant inherited disease that is characterized by multiple benign tumors of the nervous system and caused by a gene located on the q12 band of chromosome 22. Bilateral acoustic neuroma, the first symptom of which is bilateral progressive hearing loss, is the most common clinical characteristic of NF2. Clinical diagnosis of NF2 is based on the Manchester standard. There is a certain overlap between the diagnoses of schwannomatosis and NF2, the characteristics of the 2 conditions differ nonetheless: (1) they have different prevalence rates. Evans et al.’s epidemiological survey found that the prevalence of schwannomatosis is one in 126,315; that of NF2, 1 in 50,500. The calculated birth incidences were one in 68,956 and one in 27,956, respectively. (2) The onset age of NF2 is generally <30 years, while schwannomatosis is more common in the age range of 20–50 years. (3) NF2 often involves bilateral vestibular nerves, while schwannomatosis involves the skin with multiple plexiform nerves. NF2 patients also tend to develop meningiomas and spinal ependymomas, while schwannomatosis patients rarely develop intracranial meningiomas or bilateral vestibular schwannoma. (4) Life expectancy in schwannomatosis (mean age at death, 76.9 years) is significantly better than in NF2 (mean age at death, 66.2 years). (5) Farschtschi et al. measured the intraepidermal nerve fiber density (IEND) of skin biopsies and found that the IEND of patients with schwannomatosis (97%) was significantly lower than the standard reference, while fewer than half (44%) of NF2 patients had such low IEND. (6) Louvrier et al. suggested that the key to differential diagnosis between NF2 and schwannomatosis is the use of an amplification-based method to sequence tumor suppressor genes in NF2: SMARCB1, LZTR1, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 (SMARCE1) and suppressor of fused homolog (SUFU). (7) Schwannomatosis is mainly composed of Schwann cells, while the cells that comprise NF2 include Schwann cells, nerve bundle membrane-like cells, fibroblasts and intermediate cells. (8) Nerve fibers often pass through NF2 masses but not through those seen in schwannomatosis. (9) Schwannomatosis-associated schwannomas tend to exhibit greater peripheral edema, and the myxoid change in the focus shows T2 high signal. Moreover, the range of minimum apparent diffusion coefficient (ADC) values is 0.8–2.7 in NF2, 0.3–2.2 in schwannomatosis.
3.4Treatment and prognosis
Surgical resection is the most reliable treatment for schwannomatosis. Ten of our 12 patients underwent surgery. The other two declined the operation after communication with us because they had too many tumors and surgery would have been difficult.
3.5 Study limitations
The limitations of this study were as follows: (1) This was a retrospective study with a small number of cases. Because some of the diagnoses were confirmed at an early age and/or before the new diagnostic standard came into being, not all of the patients underwent lztr1 and smarcb1 gene examination for clinical diagnosis. We cannot guarantee that any of the patients with schwannomatosis did not also have mosaic NF2. Some patients with mosaic NF2 will be included in this diagnosis when they are at a young age. Some patients with schwannomatosis might have unilateral vestibular schwannoma. (2) These patients did not have 3-mm thin slice scans or whole-body MRI examinations, and it is not excluded that some masses were not found in some areas without scanning. (3) It was difficult for some patients to confirm their family histories or for us to obtain samples from their family members for genetic analysis. (4) We did not compare the imaging characteristics seen in this study with those of NF2. (5) Because treatment plan and efficacy evaluation were not the focus of this study, no corresponding discussion and case follow-up analysis was conducted.